Alpha-(3-(4-chlorobenzoyl)-2-methyl-6-methoxy-1-ndole)-acetic acid

ABSTRACT

New 3-substituted-1-indole-lower-alkanoic acids and esters having useful anti-inflammatory activity and prepared by alkylation of a 3-substituted-indole with an appropriate halolower-alkanoic acid or ester.

United States Patent [191 Field of Search 260/326.13 R

Bell Oct. 22, 1974 a-[3-(4-CHLOROBENZOYL)-2-METHYL-6- [56] References Cited METHOXY-l-INDOLEl-ACETIC ACID UNITED STATES PATENTS [75] Inventor: Malcolm R. Bell, East Greenbush, 3,505,354 4/1970 Doebel et al. 260/326.l3

FOREIGN PATENTS OR APPLICATIONS Assigneel Sterling 1311131119" New York, 1,492,929 7/1967 France 260/326.l3 [22] Filed: Nov. 22, 1971 P E J h A N rmzary xammerosep ar'cavage [2]] Appl' 201,142 Attorney, Agent, or Firm-Elmer J. Lawson; Willliam Related US. Application Data (1 Webb [63] Continuation-impart of Ser. No. 9945. Feb. 9,1970,

abandoned, which is a continuation-in-part of Ser. ABSTRACT No. 706.802, Feb. 20, 1968, Pat. No. 3,557,142. '[30] Foreign Application Priority Data New 3-substituted-i-indole-lower-alkanoic acids and esters having useful anti-inflammatory activity and DEC. 29,1969 Great Britam 7719/69 p p y alkylation of a s subsfituted indole with 521 US. Cl. 260/326 13 R 260/326.14 R an appropriate acid [51] Int. Cl C07d 27/56 [58] 1 Claim, N0 Drawings v 1 a-[3-(4-CHLOROBENZOYL)-2-METHYL-6- METHOXY-1-INDOLE1-ACETIC ACID This application is a continuation-in-partof my prior copending application Ser. No. 9,945, filed Feb. 9, 1970 now abandoned, which in turn is a continuationin-part of my prior filed application Ser.v No. 706,802, filed Feb. 20, 1968, now US. Pat. No. 3,557,142, patented Jan. 19, 1971. g

This invention relates to certain 3-substituted-1- indole-lower-alkanoic acids and esters having the for mula: v

Y-COOR where R, is hydrogen or lower-alkyl; R is hydrogen or loweralkyl; R is phenyl, benzoyl, thiophenecarbonyl, furancarbonyl, pyridinecarbonyl, isoxazolecarbonyl, thiazolecarbonyl, isothiazolecarbonyl, phenyl-loweralkyl, phenyl-lower-alkenoyl, cycloalkylcarbonyl, adamantanecarbonyl, biphenylcarbonyl, phenoxy, phenylmercapto, or phenylsulfonylmethyl; R is a hydrogen atom or a methylenedioxy 'or ethylenedioxy group attached to adjacent carbon atoms or one to three'of the same or different members of the group consisting of halogen, lower-alkyl, nitro, amino, loweralkanoylamino, di-lower-alkylamino, trifluoromethyl,

lower-alkanoyloxy, or hydroxy; and Y is loweralkylene. v

' Also within the purview of the instant invention are compounds having the formula -R l 3 -R N 2 Y-COOR where R, is hydrogen, lower-alkyl, or an alkali metal cation; R is hydrogen or lower-alkyl; R is benzoyl or benzoyl substituted by from one, to three lower-alkoxy groups or by from one to two halogen atoms; and Y is lower-alkylene containingfrom one tothree carbon atoms. Particularly preferred compounds within the genus described by formula Ia as defined above are 7 those where R is benzoyl or benzoyl substituted by a ethyl a-[ 3-( 4-chlorobenzoyl )-2-methyll indolelacetate;

a-( 3-benzoyl-2-methyll -indole)acetic acid;

sodium B-t 3-benzoyl-2-methyl -l-indole)propionate;

a-[3-( 4-methoxybenzoyl )-2-methyll -indole acetic acid; and i 1 a-[3-( 3,4-dichlorobenzoyl)-2-methyl-lindole]acetic acid. Also considered to be within the purview of the instant invention are compounds having the formula:

Hal

Y--COOR where R, is hydrogen or an alkali metal cation; R is lower-alkyl; R is benzoyl or benzoyl substituted by halogen; Hal is halogen; and Y is methylene or 1,2-

ethylene. Particularly preferred species within the a 3-benzoyl-2-methyl5-chlorol -indole )acetic acid; and B-(3-benzoyl)-2-methyl 5-chloro-l-indole)propionic acid. Also within the scope of the instant invention are compounds having the formula:

Alkoxy- -C Alkoxy- -R 1 Y- COOR where R, is hydrogen or lower-alkyl; R is lower-alkyl; each Alkoxy contains from one to six carbon atoms; and Y is lower-alkylene, and particularly preferred species within the ambit of formula lc above are:

a-( 3 benzoyl-5,6-dimethoxy-2-methyl-1- indole)acetic acid; and

B4 3-benzoyl-5 ,6-dimethoXy-2-methyll indole)propionic acid.

The compounds of formulas I, Ia, lb,.and Ic are useful as anti-inflammatory agents as more fully discussed hereinafter.

As usedherein, the term lower-alkyl" (or loweralkoxy or alkoxy") means saturated, monovalent aliphatic radicals, including straight or branched-chain radicals of from one to six carbon atoms in the alkyl moiety, as illustrated by, but not limited to, methyl,

, l,l-ethylene,

3 ethyl, propyl, isopropyl, n-butyl, t-bu'tyl, amyl, hexyl, and the like.

As used herein, the term lower-alkylene means divalent, saturated, aliphatic radicals, including straight where R5 is benzoyl or substituted-benzoyl. That is, the latter compounds are reacted with hydrazine in the 1 presence of strong alkali, e.g. potassium hydroxide, at an elevated temperature, i.e. in the range from about or branched-chain radicals of from one to six carbon 5 130 to 230C, and preferably in an alkanol, polyhyatoms, as illustrated by, but not limited to, methylene,

1,2-ethylene, 1,3-propylene, propylene, l,6-hexylene, and the like.

As used herein, the term cycloalkyl means satudroxyalkane, or glycol ether as solvent. A preferred solvent is triethylene glycol.

The compounds of formulas I, la, lb, or is where R is hydrogen can also be prepared by saponification of rated, monocarbocyclic radicals containing from three the correspondingesters where R is lower-alkyl by to six carbon atoms, as illustrated by cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyL- As used herein the term "phenyl-lower-alkenoyl means a monovalent radical derived from a phenylheating a solution of the latter in a lower-alkanol, for

example methanol, ethanol, isopropanol, and the like,

and containing a molar excess of an alkali metal hydroxide, for example sodiumor potassium hydroxide.

lower-alkenoic acid by removal of the hydroxyl group l5 The intermediate 3-substitutedwindoles of formula II from the carboxylic moiety thereof. The term phenyllower-alkenoyl includes straight or branched-chain lower-alkenoyl radicals containing from three to six carbon atoms in the lower-alkenoyl moiety, and thus where R is phenyl, phenoxy, or phenylmercapto are prepared by Fischerindole cyclization of an R -benzyl, R -phenoxymeth'yl, or R -phenylmercaptomethyl ketone (or aldehyde) phenylhydrazone according to the includes, inter alia, cinnamoyl, a-methylcinnamoyh reaction;

' III B-ethylcinnamoyl, and the'like.

The compounds of formulas I, la, lb, and Ic are prepared by reaction of an appropriate 3-substitutedindole with a haloJower-alkanoicacid or lower-alkyl ester thereof in the presence of an acid-acceptor which E F I 1;

where R and R5 have the meanings given above, and

R is understood, in this instance, to include, in addition to its particular meanings given above, the benzenoid groups in the compounds of formulas la, lb, and

Ic. The reactionis carried out by heating the hydrazone serves to t k p the hy rogen h lid pli out ring III. in the presence ofan acid, for example hydrochloric the'course of the reaction. The reaction is represented by the equation:

I I v R impoooagr,

t -R i 1 H II dimethylformarnide, and the like. A preferred solvent is dimethylformamide, and a preferred acid-acceptor is sodium hydride.

The compounds of formula I where R, is benzyl or substituted-benzyl can also be prepared by Wolff- Kishner reduction of the corresponding compounds acid, sulfuric acid, p-toluenesulfonic acid, glacial acetic acid, and the like, in an organic solvent inert under the Ia, Ib, or Ic III and generally takes place at room temperature. Like the cyclization of the hydrazones of formula Hi to the indoles of formula II, the reaction is advantageously carried out in an organic solvent inert under the conditions of the reaction,'for example methanol, ethanol,

isopropanol, and the like, and in the presence of an carbonyl are prepared by reacting the acid, forrexample hydrochloric acid, sulfuric acid,

p-toluenesulfonic acid, glacial acetic acid, and the like.

The. hydrazones of formula Ill thus formed can, if desired, be isolated from the reaction mixture before cyclizing to the indoles of formula II, but it is preferred to carry the reaction to completion, without isolating the intermediate hydrazones, by heating the reaction mixture containing the hydrazone which itself is formed at lower temperatures. I

The phenylhydrazines of formula IV and the ketones of formula V are old classes of compounds, and many .indole with a lower-alkyl magnesium halide. The

method is represented by the equations:

where R and R have themeanings given above R represents lower-alkyl, X represents halogen, and R is understood, in this instance, to include, inaddition to its particular meanings given above, the benzenoid groups common to the compounds of formulas la, lb, and lc.

The reaction is carried out at a temperature from 20C.

to about l00C. in an organic solvent inert under the conditions of the reaction, for example diethyl ether, tetrahydrofuran, dioxane, and the like.

The intermediate 3-substituted-indoles of formula II ing, with an alkali metal aluminum hydride, the corresponding compounds where R is benzoyl or phenyllower-alkanoyl. The reaction takes place'at tempera-,

tures in the range from about 20C. to about 80C. in an organic solvent inert under the conditions of the reaction, for example diethyl ether or tetrahydrofuran. It is preferred to carry out the reaction in tetrahydrofuran at theboiling point thereof.

The compounds of formula II where R is phenylsulfonylmethyl are prepared by reaction of an appropriate 3-unsubstituted indole with a phenylsulfinic acid and'formaldehyde in an acid carried out at a temperature in the range from 80C. to around 200C. in an organic solvent inert under the conditions of the reaction, for example dimethylformamide or glacialacetic acid or in a combination of these solvents.

l where R is phenyl-lower-alkyl are prepared by reduc- The compounds of formulas I, la, lb, and le where R is hydrogen are interconvertible with the compounds where R is lower-alkyl, and moreover the acids are interconvertible with salts, for example alkali metal or alkaline earth salts, or ammonium or amine salts, e.g. N-methylglucamine, and the salts are considered to be the full equivalents of the acids and esters hereclaimed. Thus the acids R is hydrogen) are prepared from the esters R is lower-alkyl) by saponification of the latter with alkali. The salts are obtained from the corresponding acids by reaction of the latter with one molar equivalent of an appropriate base, for example an alkali metal hydroxide, alkaline earth hydroxide, ammonia or an amine, and isolation of the product from a neutral or basic medium. The lower-alkyl esters (R, is lower-alkyl) are obtained from the corresponding acids by esterification of the latter with a loweralkanol in the presence of a mineral acid. The compounds of formulas I and II are antiinflammatory agents as determined in standard and recognized pharmacological tests as described hereinbelow. I I

Anti-inflammatory activity of the compounds was determined by one or more of three standards test procedures for determination of anti-inflammatory activity, namely by the inhibition of carrageenin-induced local foot edema in rats, :by the adjuvant-induced arthritis test, and by the inhibition of asbestos pellet induced granuloma test. I I

v The inhibition of carrageenin-induced local foot edema test used is generally described by Winter et al., ProcLSoc. Exp. Biol. Med. 111, 544 (1962). The tests were carried'out in fasted male Sprague-Dawley rats weighing approximately 100 tel 15 grams from which all food was withdrawn twenty-four hours prior to medmedium. The reactionis ication. The rats were divided into groups of at least five rats pergroup, and suspensions of the compounds in gum tragacanth were administered by stomach tube in a volume of 1 ml. per g. of body weight. A control group of animals received only the gum tragacanth. This treatment was followed one hour later by injection into the plantar tissue of the right hind paw of all test and control animals of 0.05 ml. of a 1 percent aqueous suspension of carrageenin. As a control, theleft hind paw was similarlyinjectedwith saline. Swelling of the carrageenin-injected paw reached a peak in from three to five hours, and the increase in swelling three hours after injection of the carrageenin was'adopted as a measure of effect. The inhibition of carrageenin induced edema in treated animals over untreated controls is then determined by procedures involving either a measure of the relative weights or volumes of the edema. One I method involving determination of the weight of the edema is that described previously in my earlier eopending application Ser. No. 706,802. A preferable method involving the determination of the volume of the edema is describedas follows: Three hours following carrageenin injection, the increase in foot volume, i.e. the edema formation the difference between the left hind paw and the uninjected right hind paw) was, measured plethysmographically. The extended paw was immersed to the top of the most proximal callus pad into a mercury filled glass cylinder connected to a pressure transducer and the impulse amplified and recorded by a polygraph. The polygraph was standardized so that a 3.6 mm. deflection on the recording paper was equivalent to 0.1 ml. volume. The results were expressed either in terms of the percent inhibition at a dose of 100 mg./kg. calculated from the average differences in foot volume between the control and medicated rats or in terms of the AED the Average Effective Dose producing 40 percent inhibition of the inflammation, the latter value being calculated from a'doseresponse curve. The compounds were thus found to have an AED in the range from 17 to 1 mg./kg. The toxicities of the compounds, expressed in terms of the Approximate Lethal Dose ALD determined on oral administration in rats, were found to be in the rangefrom 800 to -l,000 mg./kg.

The adjuvant-induced arthritis test used is a modification of that described by Pearson, J. Chronic Diseases, 16, 863(1963) and Glen et al., Am. J. Vet. Res., 26, l 180 1965). Adult male rats weighing 200-230 g. were injected into the plantar tissue of the left hind paw with 0.1 ml. of a 0.6 percent suspension of adjuvant in heavy mineral oil. A negative control group was injected with the mineral oil only. Beginning on the ninth day after injection, suspensions of the test compounds in 1 percent gum tragacanth were administered by stomach tube six times'daily to the animals in a volume of 1 ml. per 100g. of body weight. Both the negative control and the adjuvant injected control animals received the vehicle only. Food and water were permitted ad libitum, and 24 hours following the last medication, the animals were weighed, and the increase in foot volume was measured plethysrnographically. The extended paw was immersed to the top of the most proximal callus pad into a mercury filled glass cylinder connected to apressure transducer, and the impulse was amplifiedand recorded by a polygraph. The polygraph was standardized for each assay so that at 3.6 mm. de-,

flection on the recording paper was equivalent to 0.1 ml. of volume. The resultswere expressed as percent inhibition calculated from the average differences in foot volume between theadjuvant injected control and medicated rats correcting the difference in foot volume of the oil injected negative control group.

The asbestos pellet test used is a modification of the method described by Meier et al., Experientia, 6, 469 (1950). Young male'rats.weighing 100-120 g. were placed under light ether anaesthesia, and a single sterilized asbestos pellet, punched from Leitz No. 3 filter pads and weighing approximately 30 mg., was implanted subcutaneously in the interscapular area via a small skin incision and closed with a wound clip. Begin ning on the day of pellet implantation, the animals were administered by stomach tube seven daily medications of the test compound suspended in 1 percent gum tragacanth in a volume of lv ml. per 100 goof body weight. Control animals were given the vehicle only. Food and water were permitted ad libitum, and 24 hours following the last medication, the animals were weighed, sacrificed, and the pellets with surrounding granuloma were carefully removed and weighed. The results were expressed as percent inhibition of fresh granuloma weights calculated from the differences between the average granuloma weights of control and medicated rats.

Although the compounds are less active on a weightto weight basis than the known anti-inflammatory agent, l-( 4-chlorobenzoyl)-5-methoxy-2-methyl-3- indole]acetic acid indomethacin), they are relatively less toxic, i.e. have a more favorable ratio of the toxic to the active dose.

The compounds can be prepared for use by dissolving or suspending them in aqueous alcohol, glycol or oil solution, or oil-in-water emulsions in the same manner as conventional medicinal substances are prepared. Alternatively, they can be incorporated in unit dosage form as tablets or capsules for oral administrationv either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, and the like. The compounds are administered to any suitable mammalian host in a dose range of 2-100 mg./kg.

The chemical structures of the compounds of the inventionare established by their mode of synthesis and EXAMPLE 1 A. 3-Benzoylindole [11: R is H; R is C H CO; R is H] To a solution of 160 ml. of a 3M ether solution of ethyl magnesium bromide diluted with 100 ml. of absolute ether was added with stirring, over a period of 45 minutes, a solution of 50 g. (0.43 mole) of indole in 300 ml. of absolute ether while maintaining the temperature at 0-5C. The resulting yellow suspension was allowed to warm to 15C. for 30 minutes and was then cooledto 0-5C. and treated with a solution of 60 g. (0.43 mole) of benzoyl chloride in ml. of absolute ether. The mixture was then refluxed for 2 /2 hours, allowed to stand at room temperature overnight, treated with 400 ml. of saturated aqueous ammonium chloride, and the ether-soluble product was extracted with 1,500 ml. of tetrahydrofuran. The extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give a light pink solid which was recrystallized from ethyl acetate giving 50 g. of 3-benzoylindole, mp. 23 7239C. B. Ethyl oi-( 3-benzoyl-l-indole)acetate [la: R is C 11 R is R; R is C H CO; Y is CH A mixture of 20 g. (0.09 mole) of 3-benzoylindole and5.1 g. 0.1 1 mole) of a'52 percent suspension of sodium hydride in mineral oil in 250 ml. of dry dimethylformamide was stirred at room temperature for 45 minutes. The resulting orange, almost clear solution was treated all at once with 17.9 g. (0.11 mole) of ethyl bromoacetate, and the resulting solution was stirred for 2 hours and'then allowed to stand for 6 hours. The clear, red-brown solution was diluted with 2 liters of ethyl acetate, washed with three 500 ml. portions of water, once with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to give 30.2 g. of ethyl a-(3-benzoyl1-indole) acetate, which on recrystallization from ethanol gives material of m.p. 136-l38C. (uncorr.).

C. a-(3-Benzoylsl-indole) acetic acid [1a: R and R are H; R is C H CO; Y is CH i .A solution of 30.2. g. (0.10 mole) of ethyl a-(3 benzoy1-1-indole)acetate in 400ml. of ethanol and 105 ml. of 10 percent aqueous sodium hydroxide was refluxed for 2 hours, and the solvent removed by evaporation in vacuo. The residual yellow gum was dissolved in two liters of 50 percent ethanol/water and the solution acidified to pH 1 with 33 percenthydrochloric acid. The flocculent precipitate was collected, dried, and recrystallized twice from ethanol to give 18.1 g. of a-( 3-benzoyl-l-indole) acetic acid, m.p. 216-'2l8C.

, EXAMPLE 2 A. .3-Benzoyl-Lmethylindole 'n; R, is cm; R, is

C H CO; R is H] was prepared by reactionof 103 g. 0.73 mole) of benzoyl chloride with the Grignard reagent prepared from 96 g. (0.73 mole) of 2- methylindole and 275 ml. (0.82 mole) of a 3M ether solution of ethyl magnesium bromide in a totalvolume of about 950 ml. of diethyl ether using the procedure described above in Example IA. The crude product was recrystallized from ethyl acetate to give 93.5 g. of 3-benzoyl-2-methylindole, m.p. l83-184C.

B. Ethyl a-( 3-benzoyl-2-methyl-1-indole)acetate [la: R is C H R is CH ;-R is C H CO; Y is CH was prepared by reacting 20.0 g. 0.085 mole) of 3-benzoyl-2- methylindole with 17.0 g. 0.10 mole) of ethyl bromoacetate in 250 ml. of dry dimethylformamide in the presence of 4.85 g. (0.103 mole) of a 52 percent suspension of sodium hydride in mineral oil using the pro- I cedure described above'in Example 1B. There was thus obtained 35.2 g. of ethyl a-(3-benzoyl-2-methyl-lindo1e)acetate as a brown oil.

C. a-( 3-Benzoyl-2-methyl-l-indo1e)acetic acid [la: R is H; R is CH R is C H CO; Y is CH2] was prepared by saponification of 35.2 g. 0.11 mole) of ethyl a-(3-benzoyl 2-methyl-1-indole)-acetate in a solution of 400 ml. of ethanol and 100 ml. of 10 percent aqueous sodium hydroxide using the-procedure described above in Example 1C. The crude product was recrystal-v lized twice from ethanolto give 13.2 g. of a-(3- benzoyl-Z-methyl-l-indole)acetic acid, m.p. 211-212C.

EXAMPLE 3 A. Ethyl ,8-( 3-benzoy1-2 -methyl-l-indole)propionate [1a: R is C H R is CH R is C' H CO; Y is CH CH was prepared by reacting 20.0 g. (0.085 mole) of 3-benzoyl-2-methylindole'with 18.5 g. (0.102 mole) of ethyl ,B-bromopropionate in 250 ml. of dry dimethylformamide in the presence of 4.8 g. (0.103 mole) of a 52 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B.

There was thus obtained 34.0 g. of ethyl ,B-( 3-benzoyl- 2-methy1-l-indole)propionate as a brown oil.

B. [H 3-Benzoyl-2-methyl-l-indole)propionic acid [1a: R is H; R is CH R is C H CO; Y is CH CH was prepared by saponification of 34.0 g. (0.10 mole) of ethyl B43-benzoyl-2-methyl-1-indole)propionate in a 1 solution of 400 ml. of ethanol and 100 ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized twice from ethanol to give 13.5 g. of /3-( 3-benzoyl-2-methyl-l-indole) propionic acid, m.p. 205207C. Y

I EXAMPLE 4 A. 3-( 4-Chlorobenzoyl)indo1e [11: R is H; R, is 4-ClC l-1.,CO; R. is H] was preparedby reaction of 74.0 g. (0.43 mole} of 4-chlorobenzoyllchloride with the Grignard. reagent prepared from 50.0 g. (0.43 mole) of indole and 160 ml. (0.49 mole) ofa 3M ether solution of ethyl magnesium bromide in a totalvolumc of about 450 ml. of diethyl ether using the procedure described above in Example 1A. The crude product was recrystallized from ethyl acetate to give 52.6 g. of 3-(4-chlorobenzoyl)indole,'m.p. 180-200C.

B. Ethyl a-[3-chlorobenzoy1)-1-ind0le]acetate la: R is C 11 R is H; R is 4ClC H.,CO; Y is CH was prepared by reaction of 15.7 g. (0.94mo1e) of ethyl bromoacetate with 20.0 g. (0.078 mole) of 3-(4- chlorobenzoyl)indole in 250 ml. of. anhydrous dimethylformamide in the presence of 4.5 g. (0.094 mole) of a 50 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 13. There was thus obtained 31.7 g. of ethyl a-[3-(4- chlorobenzoyl)-l-indole]acetate as an off-white solid which, after recrystallization from ethanol, afforded material of m.p. 159'-161C. (uncorr.).

C. a-[3 4-Chlorobenzoyl)-1-indole]acetic acid [Ia: R a d. R2 rQHJ. R; is .iTQQlll/QQQQ He e a preparedby saponification of 31.7 g. (0.093 mole) of ethyl a-[3-(4-chlorobenzoyD-1 indolel-acetate in a solution of 400 ml. of ethanol and 'ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized once from ethanol/ benzene and once from ethanol to give 13.6 g. of a-[3-(4-chlorobenzoyl)-l-indole lacetic acid, m.p. 235-236C.

EXAMPLE 5 ,A. 3-( 4-Chlorobenzoyl)-2-methylindole [11: R is CH R is 4-CIC H CO; R is H] was prepared by reaction of 133.5 g. (0.96 mole) of 4-chlorobenzoyl chloride with the Grignard reagent prepared from 100 g. 0.70 mole)of 2 methylindole and 300 ml. (0.90 mole) of a 3M ether solution of ethyl magnesium bromide in a total volume of about 1100 ml. of absolute diethyl ether using the procedure described above in Example 1A. The crude product was recrystallized from ethyl acetate to give 157 g. of 3-(4-ch1orobenzoyl)-2- methylindole, m.p. 181-183C.

B. Ethyl a-[ 3-( 4-ch1orobenzoyl)-2-methyl- 1'- ind01e]acetate [Ia: R is C H R is CH R 4ClC H CO; Y is CH was prepared by reaction of 74.3 g. (0.45 mole) of ethyl bromoacetate with 100 g. 0.37 mole) of 3-(4-chlorobenzoyl)-2-methylindole in one liter of anhydrous dimethylformamide in the presence of 21.0 g. (0.46 mole) of 52 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B. There was thus obtained 146.4 g. of crude product as a peach colored solid of which 25 g. was recrystallized from ethanol to give 15.1 g. of ethyl oe-[3-(4-chlorobenzoyl)-2-methy1- l-indole]acetate as .a white, peach-tinted solid, m.p. -146C.

C. a-[ 3-( 4-Chlorobenzoyl)-2-methyl-1-indole]acetic acid [la: R is H; R is CH R is-4ClC H CO; Y is CH was prepared by saponification of 39 g. (0.11

mole) of ethyl a-[3-( 4-chlorobenzoyl)-2-methyl-1- indo1e]acetate in a solution of 800 ml. of ethanol and 200 m1. of 10 percent aqueous sodium hydroxide using the procedure described above ,in Example 1C. The crude product was recrystallized twice from ethanol anddried in vacuo at 100C. to give 10.6 g. of 01-[3-(4- -chlorobenzoyl)-2-methyl-l-indole]-acetic acid, m.p.

' EXAMPLE 6 A. Ethyl B-[ 3-( 4-chlorobenzoyl )-2-methyll methyl-l-indole]propionate as a yellow, viscous oil.

B-[3-( 4-Chlorobenzoyl)-2-methyll indolelpropionic acid [laz R is H; R is CH R is 4-CIC H CO; Y is CH CHQ] was prepared by saponification of 36 g. 0.098 vmole) of ethyl B-[3-( 4- chlorobenzoyl)-2-methyl-l-indolelpropionate in a solution of 800 ml. of ethanol and 200 ml. of 10 percent aqueous'sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized twice from tetrahydrofuran to give 11.0 g. of B-[3-( 4-chlorobenzoyl)-2-niethyl-.1- indole]propionic acid, m.p. 224227C. (dec.).

EXAMPLE 7 A. 3-( 3,4-Dichlorobenzoyl)-2-methylindole [11: R is CH R is 3,4Cl C H CO: R is H} was prepared by reaction of 100 g. (0.48 mole) of 3,4-dichlorobenzoyl chloride with the Grignard reagent prepared from 62.5 g. (0.48 mole) of 2-methylindole and 191 ml. (0.57 mole) of an approximately 3M ether solution of methyl magnesium bromide in a total of 800 ml. of anhydrous diethyl ether usingv the procedure described above in Example 1A. There was thus obtained 20.8 g. of 3-( 3,4- I

dichlorobenzoyl)-2 methylindole, m.p. 229230C.

3-( 3,4-Dichlorobenzoyl)-2-methylindole was studied in electrolyte'excretion modification tests in rats, and found to be active as a kaluretic agent at a dose of mg./kg. s.c. The test for electrolyte excretion modification was carried out as follows: Male Charles River CD rats weighing 180 to 195 g. were maintained in the laboratory for'one week to equilibrate them, during which time water and food were provided ad libitum. All food was removed from the cages of the test animals approximately 18 hours preceding the test, and water was removed 2% hours preceding the test. All test animals were then voided of urine by applying pressure with the fingers over the region of the bladder, and after weighing, were divided into experimental groups and placed into individual metabolism cages equipped for urine collection. All rats were then administered intraperitoneally 10 ml. of Krebs Ringer phosphate solution, and the test compound, prepared as a suspension in 10 percent ethanol-cottonseed oil, was injected subcutaneously immediately following administration of tion of p'entobarbital prior to final weighing. Urine vol-v umes were recorded in each case, and the metabolism cages were washed down with small amounts of distilled water, and the'urine samples with the water washings were diluted to 50 ml. with distilled water. Suitable aliquots were then analyzed for sodium, potassium, chloride, magnesium, phosphorus, calcium, and nitrogen by. standard analytical procedures.

B. Ethyl a-[3-( 3,4-dichlorobenzoyl )-2-methyll indole]acetate [lax R is C H R is CH R is 3,4Cl C H CO; Y is CH was prepared by reaction of 23.0 g. (0.14 mole) of ethyl bromoacetate with 35.0 g. (0.12 mole) of 3-.(3,4-dichlorobenzoyl)-2-methylindole in 250 ml. of anhydrous dimethylformamide and in the presence of 5.92 g. (0.138 mole) of a 56 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B. There was thus I obtained 48 g. of ethyl a-[3-(3,4- dichlorobenzoyl)-2-methyl-1-indole]acetate as a yellow oil.

C. a-[3-( 3,4-Dichlorobenzoyl)-2-methyl-1- indole]acetic acid [la: R is H; R is CH R is 3,4-Cl C H CO; Y, is CH was prepared by saponification of 48 g. (0.12 mole) .of ethyl a-[3-(3,4- dichlorobenzoyl)-2-methyl-l-indole]acetate in a solution of 500 ml. of ethanol and ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized three times from ethanol giving 19.5 g. of a-[3-( 3,4-dichlorobenzoyl)-2-methyl-1-indole]acetic acid, m.p.- 212214C.

EXAMPLE 8 A. 3-( 4-Chlorobenzoyl) 6-methoxy-2-methylindole [11: R is CH R is 4ClC l-l CO; R is 6-CH O] was prepared by reaction of 21.5 g. (0.123 mole) of 4- chlorobenzoyl chloride with the Grignard reagent prepared from .18 g. 0.11 mole) of 6-methoxy-2-methylindole and 64 ml. 0.12 mole) of a 2M ether solution of methyl magnesium bromide in a total volume of about 400 ml. of tetrahydrofuran using the procedure described above in Example 1A. The crude product of m.p. l45170C. consisting of 1,3-di-( 4- chlorobenzoyl)-6-rnethoxy-2-methylindole, was dissolved in ethanol and benzene and warmed gently with a solution of 6 g. of sodium hydroxide in 50 ml. of -1 0 to hydrolyze off the 1-(4-chlorobenzoyl) group introduced during the reaction. The product was recrystallized from benzene to give 3-(4-chlorobenzoyl)-6- methoxy-2-rnethylindole as pale yellow, micro crystals, m.p. 206208.5C. B. Ethyl a-[3-( 4-chlorobenzoyl)-6-methoxy-2-methyll-indole]-acetate [1: R is C 11 R is CH R is 4- ClC H CO; R is 6-CH O; Y is CH was prepared by reaction of 1.39 g. 0.019 mole) of ethyl bromoacetate with 5.2 g. 0.017 mole) of 3-(4-chlorobenzoyl)-6- methoxy-Z-methylindole in the presence of 0.88 g. 0.019 mole) of a 52 percent suspension of sodium hydride in mineral oil in 50 ml. of dimethylformamide using the procedure described above in Example 18. There was thus obtained 6 g. of ethyl a-[3-( 4- chlorobenzoyl )-6-methoxy-2-methyll -indole acetate as a'light brown gum. C. a[ 3-( 4-Chlorobenzoyl)-6-methoxy-2-methyll indole]acetic acid [1: R is 171; R is CH R is 4ClC H CO; R is 6CH O; Y is CH was prepared by saponification of 6 g. 0.016 mole) of ethyl a-[3-( 4- chlorobenzoyl )-6-methoxy-2-methyl-' l -indole acetate in a solution of 400 ml. of ethanol and 50 ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized from ethanol to give 4.0 g. of a-[3- 4-chlorobenzoyl)-6-methoxy-2-methyl-1- indole]acetic acid, m.p. 230.514 234C.

EXAMPLE 9 A. 3-( 4-Methylbenzoyl)-2-methylindole [11: R is CH R is 4- -CH C H CO'; R is H] was prepared by reaction of 59 g. (0.38 mole) of 4- methylbenzoyl chloride with the Grignard'reagentprepared from 50 (0.38 mole) of 2-methylindoleand 140 ml. (0.42 mole) of a 3M ether solution of ethyl magnesium bromide ina total of about 550 ml. of absolute diethyl ether using the procedure described above in Example 1A. The crude product was recrystallized from ethyl acetate to give 67 g. of 3-(4-methylbenzoyl)42-methylindole, m.p. 202-204.5C. B. Ethyl a-[3-(4-methylbenzoyl)-2-methyl-l indole]acetate [1: R is C H .R is CH R5 is 4 -CH C H CO; R is H; Y is CH was prepared by reaction of 23.4 g. 0.14 mole) of ethylbromoacetate with 32 g. (0.13 mole) of 3-(4-methylbenzoyl)-2- methylindole in the presence of 5.4 g. (0.14mole) of a 62 percent suspension of sodium hydride in mineral oil in 250 ml. of dimethylformamide using the procedure described above in Example 18. There was thus obtained 62 g. of ethyl a-[3-( 4-methylbenzoyl)-2- methyl-l-indole1acetate as a yellow solid.

C. a-[3-(4-Methylbenzoyl)-2?methyl-l'-indole]acetic acid [1: R is H; R is CH R is 4-CH C H CO; R is H; Y is CH was prepared by saponification of 62 g. (0.19 mole) of ethyl a-[ 3-( 4-methylbenzoyl)-2-methyll-indole1acetate in a solution of 450ml. of ethanol and 125ml. of SSpercent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized three times from ethanol to give 2 l .5 g. of a-[ 3-( 4 -methylbenzoyl)-2-methyll-indole]acetic acid, m.p. 226229.5C. (dec.).

EXAMPLE 10 A. 3-( 4-Methoxybenzoyl) 2-methylindole [11: R is CH R is 4--CH OC H CO; R is H] was prepared by reaction of 75.9 g. 0.45 mole) of 4- methoxybenzoyl chloride with the Grignard reagent prepared from 50 g. (0.38 mole) of 2-methylindole and 'l 50 ml. (0.45 mole) of a 3M ether solution'of ethyl magnesium bromide in a total of about 550'ml. of absolute ether using the procedure described above in Example 1A. There was thus obtained 1 l 1.4 g. of 3-( 4-methoxybenzoyl)-2- methylindole. B. Ethyl a- 3-( 4-methoxybenzoyl )-2-methyll OC H CO; Y is CH was prepared by reaction of 18.9

g. (0.113 mole) of ethyl bromoacetate with 25 g; (0.09 mole) of 3-( 4-methoxybenzoyl)-2-methylindole-in the presence of 5.3 g. (0.11 mole) of a 52 percent suspension of sodium hydride in mineral oil in 250 ml. of anhydrous dimethylformamide using the procedure described above in Example 1B. There was thus obtained 41 g. of ethyl a-[3-(4-methoxybenzoyl)-2-methyl-1- EXAMPLE 1 l A. 3-(4-Trifluoromethylbenzoyl)-2-methylindole [ll:

by reaction of 50.0 g. 0.24 mole) of 4-trifluoromethylbenzoyl chloride with the Grignard reagent prepared by reacting 32.2 g. (0.24 mole) of 2-methylindole with 100 ml. 0.30 mole) of a 3M ether solution of methyl magnesium bromide in a total volume of about 375 ml. of absolute diethyl ether using the procedure described above in Example 1A. The crudes product was recrystallized twice from ethyl acetate to give 42 g. of 3-(4- trifluoromethylbenzoyl)-2-methylindole, m.p. l197C.

3-( 4-Trifluoromethylbenzoyl)-2-methylindole, in standard serial dilution anti-bacterial tests, was found to be bacteriostatic against the organism Staphylocoo cus aureus at a concentration of 0.075 mg./ml. Antibacterial activity was determined using standard serial dilution tests as described, for example, by Bailey et al., J. Am. Pharm. Assn., Sc. Ed., 48, 212 (1959). B. Ethyl a-[ 3-('4-trifluoromethylbenzoyl)-2-methyll indole]-'acetate [1: R, is C H R is CH R is 4--CF. C l-I.,CO; R is H; Y is CH was prepared by reaction of 10.95 g. (0.099 mole) of ethyl bromoacetate with 250g. (0.083 mole) of 3-(4-trifluromethylbenzoyl)-2-methylindole in the presence of 4.25 g. (0.099 mole) of a 56 percentsuspension of sodium hydride in mineral oil in 500 ml.- of dimethylformamide using the procedure described above in Example 13. The crude product was recrystallized three times from ethanol to give 3.5 g. of ethyl a-[3-( 4-trifluor omethylbenzoyl)-2- methyl- 1 -indole]acetate,'m.p. l28-- l 32C. C. a-[3-( 4-Trifluoromethylbenzoyl )-2-methyll indole]a cetic acid [1: R is H; R is CH R is 4-CF C H CO; R isI-I; Y is CH was prepared by saponification of 28 g. 0.72 mole) of ethyl a-[3-( 4- trifluoromethylbenzoyl)-2-methyl-l -indole]acetate in a solution of '400 ml. of ethanol and. ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized from ethanol to give 2.7 g. of (IE-[3- 4-trifluoromethylbenzoyl )-2-methyll -indole]acetic acid, m=p. 228-23lC. (dec.).

EXAMPLE 12 A. Ethyl B-(3-benzoyl-l-indole)propi onate [Iaz R is C H R is H; R is C H CO; Y is CH CH was prepared by reacting 19.0 g. (0.086 mole) of 3- benzoylindole with 20 g. (0.12 mole) of ethyl B-bromopropionate in 250 ml. of dimethylformamide in the presence of 5.0 g. of a 52 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B. There was thus obtained 27.7 g. of ethyl B-( 3-benzoyl-l-indole)propionate as a brown oil. t B. B4 3-Benzoyl-l-indole)propionic acid [la: R and R are H; R is C H CO; Y is CH CH was prepared by saponification of 27.7 g. (0.086 mole) of ethyl B-( 3-benzoyll -indole)propionate in 400 ml. of ethanol and 100 ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized twice from ethanol giving 6.5 g. of B-(3-benzoyl-1-indole)propionic acid, m.p. 193C.

EXAMPLE 13 volume of about 350 ml. of absolute ether using the procedure describedabove in Example 1A. The crude product was recrystallized from ethyl acetate to give 36.5 of 3-cinnamoyl-2-methylindole, m.p. 153.5'l56.5-C. (resolidifies and melts at 166l68C.).

B. Ethyl a-( 3-cinnamoyl-2-methyl-1-indole)acetate [1: R is C H R isCH R is C H CH=CHCO; R is H; Y is CH was prepared by reacting 16.6 g. (0.062 'mole) of 3-cinnamoyl-2-methylind0le with 11.3 g. 0.068 mole) of ethyl bromoacetate in 125 ml. of dry dimethylformamide in the presence of 2.68 g. (0.069 mole) of a 62 percent suspension of sodium hydride in mineral oil using the procedure described above in Example lB. There was thus obtained 20 g. of ethyl a-( 3- cinnamoyl-Z-methyl-l-indole)acetate, m.p. 1101l2C.

the presence of 2.23 g. (0.056 mole) of a 61 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B. There was thus obtained ethyl a-( 3-benzoyl-2-methyl-5,6- dimethoxy-l-indole)acetate as a pale yellow solid.

C. oz-( 3-Benzoyl-2-methyl-5,6-dimethoxy-1- indole)acetic acid [Icz R, is H; R is CH each Alkoxy is C11 Y is CH was prepared by saponification of the ethyl a-( 3-benzoyl-2-methyl-5,6-dimethoxyl indole)acetate described above in Example 158, in a solution containing 30 g. of potassium hydroxide in 200 C. a-(3-Cinnamoyl-2-methyl-l -indo1e')acetic acid [1: Y

R; is H; R is, CH R is C H CH=CHCO; R is H; Y is CH was prepared by saponification of 20 g. (0.058 mole) of ethyl a.-( 3-cinnamoyl-2-methyl- 1- indole)acetate in a solution containing 30 g. of potassium hydroxide in 250 ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from ethanol to give 9.6 g. of a-( 3-cinnamoyl-2-methyl-1-indole)acetic acid, m.p. 220-225C.

' EXAMPLE 14 A. Ethyl indole)propionate [1: R is C H R is CH R is C H CH=CHCO; R is H; Y is CH CH was prepared by reacting 14.5 g. (0.056 mole) of 3-cinnamoyl-2- methylindole with 11.05 g. (0.061 mole) of ethyl B-bromopropionate in 100 ml. of dry 'dimethylform amide in the presence of 2.42 g. 0.061 mole) of a 61 percent suspension of sodium hydride in mineral oil using the procedure described above, in Example 18. There was thus obtained 20 g. of ethyl B-( 3-cinnamoyl- 2-methyl-l-indole)propionate as a yellow gum.

B. B-( 3-Cinnamoyl-2-methyl-lindole)propionic acid [1: R is H; R is CH R is C H CH=CHCO; R is H; Y is CH CH was prepared by saponificationof 20 g. (0.063 mole) of ethyl B-(3-cinnamoyl-2-methyl-lindole)propionate in a solution containing 30 g. of potassium hydroxide dissolved in 200 ml. of methanol using the procedure described above in Example 1C.

EXAMPLE A. 3-Benzoyl-2-methyl-5,6-dimethoxyindole [11: R is CH R is C H CO; R is 5,6(CH O) was prepared by reaction of 14.0 g. (0.1 mole) of benzoyl chloride with the Grignard reagent prepared from 19.1 g. (0.1 mole) of ,2-methyl-5,o-dimethoxyindole and 37 ml. 0.1 1 mole) of a 3M ether solution of ethyl magnesium bromide in a total volume of 150 ml. of tetrahydrofuran using the procedure described above in Example 1A. The crude product was recrystallized from ethanol giving 6.1 g. of 3-benzoyl-2-methyl-5,6-dimethoxyindole, m.p. 2l0-2l2C.

B. Ethyl a-(3rbenzoyl-2-methyl-5,6-dimethoxy-1- indole)acetate [lcc R is C H R is CH each Alkoxy is CH O; Y is CH was prepared by reacting 15 g. 0.05 1 mole) of 3-benzoyl-2-methyl-5,6- dimethoxyindole with 9.35 g. 0.056 mole) of ethyl bromoacetate in 120ml. of dry dimethylformamide in ,B-(3-cinnamoyl-2-methyl-1- ml. of ethanol usingthe procedure described above in Example 1C. The crude product was recrystallized from ethanol and dried in vacuo at 100C. to give 1 1.5 g. of a-( 3-benzoyl-2-methyl-5 ,6-dimethoxyl indole)acetic acid, melts partially at 138l40C., resolidifies and melts again at 189-191C.

EXAMPLE 16 A. Ethyl B-( 3-benzoyl 2-methyl-5 ,6-dimethoxy- 1 indole)propionate [lcz R, is C H R is CH each Alkoxy is C11 0; Y is CH CH was prepared by reacting 16 g. (0.054 mole) of 3 -benzoyl-2-methyl-5,6- dimethoxyindole with 10.3 g. (0.057 mole) of ethyl B-bromopropionate in 100 ml. of dry dimethylformamide in the presence of 2.36-g. (0.06 mole) of a 61 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B. There was thus obtained ethyl ,B-( 3-benzoyl-2-methyl- 5,6-dimethoxy-1-indole)-propionate as a light brown gum. B. B-( 3 -Benzoyl-2-methyl-5 ,6-dimethoxy-1- indole)propionic acid [10: R is H; R is CH each Alkoxy is CH O; Y is CH CH was prepared by saponification of the ethyl B-( 3-benzoyl-2-methyl-5,6- dimethoxy-l-indole)propionate obtained above in Example 16A in a solution containing 30 g. of potassium hydroxide in 200 ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from ethanol to give 12.7 g. of B-( 3- benzoyl-Z-methyl-S ,6-dimethoxy-1-indole)propionic acid, m.p. 198201C.

EXAMPLE 17 A. Ethyl ,B-[3-( 4-methylbenzoyl)-2-methyl-1- indole]propionate [1: R is C H R is Ch R is 4C1-l C H CO;,R is H; Y is CH CH was prepared by reaction of 32 g. (0.13 mole) of 3-(4-methylbenzoyl)-2-methylindole with 25.4 g. 0.14 mole) of ethyl B-bromopropionate in 250 ml. of dimethylformamide in the presence of 5.4 g. (0.14 mole) of a 62 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 18. There was EXAMPLE 18 A. 3-( 2,6-Dimethoxybenzoyl)-2-rnethylindole [11: R is R3 18 R4 is was pre- 17 pared by reaction of 76 g. (0.38 mole) of 2,6-

dimethoxybenzoyl chloride with the Grignard'reagent prepared from 50 g. (0.138 mole) of Z-methylindole and 138 ml. (0.38 mole) of a 3M ether solution of ethyl methylindole with l1.3 g. 0.068 mole) of ethyl bromoacetate in 150 ml. of dry dime'thylformamide in the presence of 3 0.068 mole) of a 54 percent suspension of sodiumhydridein mineral oil using the procedure described above in Example 1B. There was thus obtained ethyl a-[3-( 2,6-dimethoxybenzoyl)-2-methyll-indolc} acetate.

C. a-[3-( 2,6-Dimethoxybenzoyl )-2-methyl-,l indole]acetic acid ethanolate [Ia: R is H; R isCH R is 2. 6(CH O) C H CO; Y isCH was prepared by saponification of f the .ethyl (Jr-[342,6- dimethoxybenzoyl)-Z-methyl-l indole]acetate obtained above in Example 18B is in asolution containing 60 g. of potassium hydroxide in 450ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from ethanol to give 1 8 g. of or-I 3 2,6-dimethoxyb enzoyl)-2-methyll indole]-acetic acid ethanolate as a white crystalline solid, mp. 250C. ('dec.).

EXAMPLE 19 A. Ethyl /3[ 3-( 2,6-dimethoxybenzoyl)-2-methyll indole]propionate [Iaz R is C H R is CH R is 2,6-( CH O) C H CO; Y is CH CH was prepared by reaction of 18 g. (0.06 mole) of 3 2,6-dimethoxybenzoyl)-2-methylindole with 12.1 g. 0.067mole) of ethyl B-bromopropionate in 150 ml. of dimethylformamide in the presence of 2.3. g. 0.061 mole) of a 62 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 1B. There was thus obtained g. of ethyl B-[3-( 2,6- dimethoxybenzoyl) 2-methyl-l-indole]propionate as an off-white solid.

B. B- [3-( 2,6-Dimethoxybenzoyl)-2-methyll indole]propionic acid [Iaz R is H; R is CH R is 2,6-( CH O) C H CO; Y is CH CH was prepared by saponification of 20 g. 0.051 mole) of ethyl B-[3-( 2,6- dimethoxybenzoyl)-2-methyl-1-indole]propionate in a solution containing 75 g. of potassium hydroxide in 500 ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from ethanol to give 9 g. of /3-'[3-(2,6-

dimethoxybenzoyl)-2-methyl-l-indole]propionic acid as an off-whitesolid, m.p. l95-l97.5C. 1

.EXAMPLE 20 A. 3-(4-Nitrobenzoyl)-2-methylindole [11: R is CH R is 4-NO C H CO; R is H] was prepared by reacting 71 g. (0.38 mole) of 4-nitrobenzoyl chloride with the Grignard reagent prepared from 50 g. 0.38 mole) of 2-methylindole and 138 ml. (0.41 mole) ofa 3M ether solution of ethyl magnesium bromide in a total of 400 ml. of absolute ether using the procedure described above in Example 1A. The crude product was recrystallized from ethanol to give 96 of 3-(4nitrobenzoyl)-2-methylindole, mp. 230C. B. a-[3-(4-Nitrobenzoyl)-2-methyll-indoleJacetic ample 1B, and saponification of the resulting ethyl a-l 3-( 4 -nitrobenzoyl)-2-methyl-I-indole]-acetate. m.p. l56158.5C. uncorr.) recrystallizedfrom ethanol), in a solution containing .20 g. of potassium hydroxide in 200 ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from acetonitrile to givea-[3-( 4 -nitrobenzoyl)-2- methyl-lfindolelacetic acid as a yellow solid.

EXAMPLE 21 a-(3-Benzoyl-2-methyl-1-indole)pr opionic acid [laz R is H; R is CH R .is C H CO; Y iSCHgCH] was prepared by reaction of 23.5 g. 0.1 mole) of 3-benzoyl-2- meth'ylindole with,18.1- g. 0.1 mole) of ethyl a-bromopropionate'in 200 mll. of dry dimethylformamide in the presence of 3.94 g. 0.1 mole) of a 61 percent suspension of sodium hydride in mineral oil using the procedure describedabove in Example 1B, and saponification of the resulting ethyl a-( 3-benzoyl-2-methyl-lindole)propionate in a solution of 50 g. of potassium hydroxide in 500 ml. of methanol using the procedure described above in Example 1C; The crude product was recrystallized fromabsolute ethanol to give 8.5 g. of a-(3-benzoyl-2-methyl-l-indole)-propionic acid, m.p. 225-227C.

EXAMPLE 22 a- 3-( 4-Chlorobenzoyl)-2-methyl-l-indole1propionic [lat R1 iS R2 iS R3 iS Y iS CH CH] was prepared by reaction of 20 g. (0.074 mole) of 3-( 4-chlorobenzoyl)-2-methyl-indole with 13.3 g. (0.074 mole) of ethyl a-bromopropionate in 200 ml. of dimethylformamide in the presence of 3.0 g. 0.075 mole) of a 61 percent suspensionof sodium hydride in mineral oil using the procedure described above in Example 1B, and saponification of the resulting ethyl a-[ 3-( 4-chlorobenzoyl)-2-methyl-1-indole]- propionate in a solution of 50 g. of potassium hydroxide in 400 ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from ethanol/water to give a-[3-( 4- EXAMPLE 23 A. 3-(4-Chlorobenzoyl)-2-methyl-5-fluoroindole [11: R is CH R is 4-ClC H CO; R is 5-F] was prepared by reaction of 25 g. (0.14 mole) of 4-chlorobenzoyl chloride with the Grig'nard reagent prepared from 12 g. (0.08 mole) of Z-methyl-S-fluoroindole and 30 ml. (0.09 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about ml. of tetrahydrofuran using the procedure described above in Example 1A. There was thus obtained 8 g. of 3-( 4-chlorobenzoyl)-2- methyl- S-fluoroindole, m.p. 23l-233C.

B. a[3-( 4-Chlorobenzoyl)-2-methyl-5-fluoro-1- indolelacetic acid [lbz R is H; R is CH R is 4'ClC H.,CO; Hal is 5-F; Y is CH was prepared by reaction of 2.4 g. (0.014 mole) of ethyl bromoacetate 1'9 7 with 4 g. (0.015 mole) of 3-( 4-chlorobenzoyl)-2-methyl-5 fluoroin'dole in 40ml. of dimethylformamide. in the presence of 0.6 g. (0.015 mole) of a 60 percent suspension of sodium hydride inmineral oil, and saponification'of the resulting ethyl oi-[3-( 4-chlorobenzoyl)-2- methyl-S-fluoroindole]acetate in a solution containing g. of potassium hydroxide in 100 ml. of methanol all according to the procedure described above in Example 1B and C. There was thus obtained 4.8 g. of a-[3- 4-chlorobenzoyl)-2-methyl-5-fluorol -indole ]acetic acid which was converted to the sodium salt by dissolving the acidform in dilute sodium hydroxide and precipitating the salt by dilution of the solution with acetone.

EXAMPLE24 B -[3-( 4-Chlorobenzoyl)-2-methyl-5-fluorol indole]propionic acid [1b:- R is H; R is CH R is 4-ClC l-l CO; Hal is S-F; Y is CH CH was prepared by reaction of 2.5 g. (0.014 mole) of ethyl-B-bromopropionate with 3.8 g (0. 14 mole) of 3-( 4-chlorobenzoyl)- 2-methyl-5-fluoroindole in 35 ml. of dimethylformamide in the presence of 0.58 g. (0.15mole) of a 60 percent suspension'of sodium hydride in mineral oil, and saponification of the resulting ethyl B-[3-( 4- chlorobenzoyl )-2-methyl-5 -fluoro-l-indole1propionate in a solution, containing 12 g. of potassium hydroxide in 100 ml. of methanol all according to the procedure described above in Example 13 and C. The crude product was recrystallizedtwo times from acetonitrile to give 3.3 g. of B -[3-( 4-chlorobenzoyl)- 2-methyl-5- fluoro-1-indole]propionic acid, m.p. 205-207C.

EXAMPLE 25 A. 3-Benzoyl-2-rnethyl-5-fluoroindole [Ilz R is'CH R is C H CO; R is 5-F] was prepared by. reaction of 22.5 g. (0.16 mole) of benzoyl chloride with the Grignard reagent prepared from 12 g. 0.08 mole) of 2-methyl-5- fluoroindole and 30 ml. 0.09 mole) of a 3M ether solution of ethyl magnesium bromide in a total volume of about 100 ml. of tetrahydrofuran using the procedure described above in Example 1A. The crude product was recrystallized from methanol to give 8.6 g. of 3- benzoyl-2-methyl-5-fluoroindole, m.p. 232.234C.

B. a-( 3-Benzoyl-2-methyl-5-fluoro-1-indole)acetic acid [lbz R is H; R is CH;,', R is C H CO; Hal is S-F; Y is CH was prepared by reacting 2.9 g. (0.017 mole) of ethyl bromoacetate with 4 g. (0.017 mole) of 3- benzoyl-2-methyl-5-fluoroindole in 40 ml. of dimethylformamide in thepresence of 0.68 g. 0.017 mole) of a 60 percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl a-( 3- benzoyl-2-methyl-5-fluoro-1-indole)acetate in a solution containing 10 g. of potassium hydroxide in 100 ml. of methanol all according to the procedure described above in Example 13 and C. The crude product was recrystallized two times from acetonitrile to give 2.2 g. of a-(3-benzoyl-2-methyl-5-fluorol-indole)acetic acid, m.p. 253255C.

EXAMPLE 26 B-( 3-Benzoyl-2-methyl-5-fluorol -indole )propionic acid [lbz R, is H; R is CH R is C H CO; Hal is S-F;

(0.018 mole) of a 60 percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl B-( 3-benzoyl-2-methyl-5-fluorol indole)propionate in a solution containing 12 g. of potassium hydroxide in 100 ml. of methanol all according to the procedure described above in Example 18 and C. The crude product was recrystallized two times from acetonitrile to give 3.4 g. of B-( 3-benzoyl-2-methyl-5- fluoro-1-indole)propionic acid, m.p. 228-230C.

EXAMPLE 27 A. 3-( 2,6-Dichlorobenzoyl)-2-methylindole [11: R is CH R is 2,6-Cl C H CO; R is H] was prepared by reaction of 105 g. (0.5 mole) of 2,6-dichlorobenzoyl mide in a total volume of about 600 ml. of absolute diethyl ether and ml. of tetrahydrofuran using the procedure described above in Example 1A. The crude product was recrystallized from ethanol to give 50 g. of 3( 2,6-dichlorobenzoyl)-2-methyl-indole, m.p. 131133C.

B. a 3-( 2,6-Dichlorobenzoyl)-2-methyll indole]acetic acid [lac R is- H; R is CH R is 2,6Cl C -H CO; Y is CH was prepared by reaction of 9.8 g. (0.057 mole) of ethyl bromoacetate with 17 g. (0.056 mole) of 3-( 2,6-dichlorobenzoyl)-2- methylindole in ml. of dimethylformamide in the presence of 2.2 g. 0.054 mole) of a 60 percent suspensionof sodium hydride in mineral oil, and saponification of the resulting ethyl a-[3-( 2,6- dichlorobenzoyl)-2-methyl-1-indole]acetate in a solution of 30 g. of potassium hydroxide in 400 ml. of hot methanol all according to the procedure described above in Example 1B and C. The crude product was recrystallized from an ethyl acetate/cyclohexane mixture giving 8.9 g. of a-[3-( 2,6-dichlorobenzoyl)-2-methyl-lindole]acetic acid, m.p. 242- 243C.

EXAMPLE 28 B-[3-( 2,6-Dichlorobenzoyl)-2-methyl-lindole1propionic acid [la: R is H; R is CH R is 2,6.Cl C H CO; Y is CH CH was prepared by reaction of 10.1 g. 0.056 mole) of ethyl B-bromopropionate with 17 g. 0.56 mole) of 3-( 2,6-dichlorobenzoyl)- Z-methylindole in 150 ml. of anhydrous dimethylformamide in the presence of 2.2 g. (0.055 mole) of a 60 percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl B-[3 (2,6- dichlorobenzoyl )-2-methyl- 1 -indole lpropionate in a solution containing 30 g. of potassium hydroxide in 350 ml. of methanol all according to the procedure described above in Example 1B and C. The crude product was recrystallized from an ethyl acetate/cyclohexane mixture to give 12 g. of B-[2,6-dichlorobenzoyl)-2- methyl-l-rindole]propionic acid, m.p. l94-196C.

EXAMPLE 29 B-( 3-Benzoyl-2-methyll -indole )-a-methylpropionic acid [-la: R is H; R is CH;,; R is C H CO; Y is CH CH(CH )]was prepared by reaction of 8.4 g. (0.043 mole) of ethyl a-bromoisobutyrate with 10 g. 0.043mole) of 3-benzoyl-2-methylindole in 100 ml. of anhydrous dimethylformamide in the presence of 1.7 g. 0.043 mole) of a 60 percent suspension of sodium hydride in mineral oil, and saponification of the resulting 21 ethyl B-( 3-benzoyl-2-methyl-1- indole)-a-methylpropionate in a solution containing 30 g. of potassium hydroxide in 300 ml. of methanol all according to the procedure described above in Example 18 and C. Theproduct was recrystallized once from isopropanol and once from ethyl acetate to give 3.5 g. of B-( 3-benzoyl-2-methyl-l -indole)-a-methylpropionic acid, m.p.'194-l96C.

EXAMPLE so A. 3-( 2-Thenoyl)-2-methylindole [11: R 'is CH R is 2C.,H S-CO; R is H] was prepared by reaction of 57 g. (0.38 mole) of thiophene-2-carboxylic acid chloride with the Grignard reagent prepared from 50 g. (0.038 mole) of 2-methylindole and 138 ml. (0.41 mole) of a 3M ether solution of ethyl magnesium bro mide in a total of 600 ml. of absolute diethyl ether using the procedure described above in Example 1A. The crude product was recrystallized from ethanol to give 37 g. of 3-( 2-thenoyl)-2-methylindole, m.p. l65167C. uncorr.).

B. a-[3-(2-Thenoyl)-2-methyl-1-indole]acetic acid [1: R is H; R is CH R is 2-C H S CO; R is H; Y is CH was preparedby'reaction of 6.7 g. (0.04 mole) of ethyl bromoacetate with g. 0.04 mole) of 3-( 2- thenoyl)-2'methylindole in 100 ml. of anhydrous dimethylformamide in the presence of 1.65 g. (0.04 mole) of a 60 percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl a-[3-(2-thenoyl)-2-methyl-l-indole]acetate in a solution of potassium hydroxide in methanol all according to the procedure described above in Example 18 and C. The crude product was recrystallized from acetonitrile to give 8.6 g. of a-[3-( 2- thenoyl)-2-methyl-1-indole]acetic acid,' mp. 227229C. uncorr.).

EXAMPLE 31 a-[3-(2-Thenoyl)-2-methyl?1-indole]propionic acid [1: R is 1-1; R is CH R is 2-C H S-CO; R is H; Y is CH C1-1] was prepared by reaction of 7.5. g. (0.04 mole) of ethyl a-bro'mopropionate with 10 g. (0.04 mole) of 3-(2-thenoyl)Q-methylindole in 100 ml. of dry dimethylformamide in the presence of 1.65 g. 0.04 mole) of a 60 percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl a-[3-(2-thenoyl)-2-methyl-l-indole]propionate in a solution containing potassium hydroxide in methanol all according to the procedure described above in Example 1B and C.

EXAMPLE 32 ,8-[3-( 2-Thenoyl)-2-methyl-1-indole]propionic acid [1: R is H; R is CH R is 2-C H SCO; R is H; Y is CH CH was'prepared by reaction of 7.5 g. (0.42 mole) of ethyl B-bromopropionate with 10 g. (0.042 mole) of 3-(2-thenoyl)-2-methylindole in 100 m1. of dry dimethylformamide in the presence of 1.75 g. 0.045 mole) of a 61 percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl B-[3 2- thenoyl)- 2-methyl-1-indole]- propionate in a solution containing potassium hydroxide in methanol all according to the procedure described above in Example 1B and C. The crude product was recrystallized once from ethyl acetate and once from acetonitrile to give 4.4 g. of B-[3-(2-thenoyl)-2-methyl-lindole]propionic acid, m.p. l69170C. (uncorr.).

EXAMPLE 33 A. Ethyl a-[ 3-( 4-aminobenzoyl)-2-methyl-1 indole]acetate [1: R, is C H R is Ch R is 4"NH2C6H4C0: R4 is Y lS Ten grams (0.027 mole) of ethyl a-[3-(4- nitrobenzoyl)-2-methyl-1-indole1acetate were dissolved in 200 ml. of ethyl. acetate and 50 ml. of methano] and reduced with hydrogen at room temperature in a Parr shaker over 1 g. of a 10 percent palladium-oncharcoal catalyst using an initial hydrogen pressure of about 50 pounds p.s.i. When reduction was complete, the'catalyst was removed by filtration, the filtrate taken to dryness, and the residue recrystallized from a chloroform/hexane mixture giving 10 g. of ethyl a[3-( 4- aminobenzoyl )-2-methyl- 1 -indole acetate, m.p. 88.5C.

a- 3-( 4-Aminobenzoyl)-2--methyl-1-indole]acetic acid [1: R is H; R is CH R is 4-NH C H CO: R is H; Y is CH is prepared by saponification of the ethyl a-[3-( 4-arninobenzoyl)-2-methyl-l-indolelacetate obtained above in Example 33A in ethanolic sodium hydroxide using the procedure described above in Example 1C.

EXAMPLE 34 A. 3-Benzoyl-2-t-butylindole [11: R is (CH C; R is R4 is A mixture of 54 g. 0.5 mole) of phenylhydrazine and 50 g. (0.5 mole) of pinacolone in 300 ml. of benzene was refluxed for seven hours under a Dean-Stark trap, during which time 6 ml. of water was collected. The resulting solution was taken to dryness in vacuo, and the resulting light brown liquid was heated slowly to C. with 400 g. 2.93 moles) of anhydrous zinc chloride. The heating bath was-then removed, and the temperature of the reaction mixture rose rapidly to C. The mixture was cooled in a water bath to 130C. and then heated for 20 minutes at C. After cooling, the mixture was mixed with water and ethyl acetate, the organic phase was separated, washed once with dilute acid, once with dilute sodium bicarbonate, and once with saturated brine. After drying the organic solution over anhydrous sodium sulfate, the solution was taken todryness, and the residual brown oil was distilled in vacuo, the product being collected at 8595,C./- 0.05 mm. There was thus obtained 46 g. of 2-t-butylindole as a colorless solid, mp. 6569C.

Reaction of 31 g. (0.22 mole) of benzoyl chloride with the Grignard reagent prepared from 19 g. 0.11 mole) of the 2-t-butylindole prepared above and 40 ml. (0.12 mole) of a 3M ether solution of ethyl magnesium bromide in a total of 210 ml. of tetrahydrofuran using the procedure described above in Example 1A, and recrystallization of the crude product from ethanol gave 3-benzoyl-2-t-butylindole, m.p. 2 l 5-220 C. B. a-(3-Benzoyl-2-t-butyl-l-indole)acetic acid [1a: R is H; R is (CH C; R is C H CO; Y is CH is prepared by reaction of the 3-benzoyl-2-t-butylindole obtained above in Example 34A with ethyl bromoacetate in dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-( 3 benzoyl-2-t-butyl-l-indole)acetate all according to the procedure described above in Example 1B and C.

EXAMPLE 35 B-( 3-Benzoyl-2-t-butyl-1-indole)pr opionic acid [Iaz R scribed in Example 13 and C.

. EXAMPLE 36 A. 3-( 4-Chloroben'zoyl)-2-t-butylindole [11: R is (CH C; R is 4CIC H CO; R is H] is prepared by reaction, in anhydrous ether or tetrahydrofuran, of 4- chlorobenzoyl chloride with the Grignard reagent prepared from 2 -t-butylindole and methylmagnesium bromide using the procedure described abovein Example 1 A B. a-[3-( 4-Chlorobenzoy1) 2-t-butyl-1-indole]acetic acid [Ia.' R is H;'R is (CH C; R is 4C1C 6 H CO; Y is CH is prepared by reaction of ethyl bromoacetate with 3-( 4-chlorobenzoyl)-2-t-buty1indole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[3- 4chlorbenzoyl)-2-t-butyl- 1 -indole]acetate all according to the procedure described above in Example 18 and .C.

EXAMPLE 37 EXAMPLE 3:;

B-[3-( 4-Nitrobenzoyl)-2-methyl-l-indolelpropionic acid [1: R is -H; R is CH R is. 4-NO C H CO;'R is H; Y is CH CH was prepared by reaction of 30.8 g. 0.17 mole) of ethyl B-bromopropionate with 45.5 g. (0.163 mole) of.3 (4-nitrobenzoyl1-2-methylindole in 300 ml. of dry dimethylformamide in the presence of 7.05 g. (0.178 mole) of a 61 percentsuspension of sodium hydride in mineral oil, and saponification of the resulting ethyl indole'] propionate, m.p. 9294C. (uncorr.) (recrystallized from ethanol) all according to the procedure described above in Example 1B and C. The crude product was recrystallized from acetonitrile to give 10.3 g. of a-[ 3-( 4-nitrobenzoyl)-2-methyl-1-indole]propionic acid, m.p. 244246C. (uncorr.)

EXAMP E 39 {3-[3-( 4-Aminobenzoy1)-2-methy1- l'-indo1e]propionic ,8-[ 3-( 4-nitrobenzoyl)-2-methyl-1-- EXAMPLE 40 B-[ 3-( 4-Dimethylaminobenzoyl)-2-methyll indole]propionic acid [1: R is H; R, is CH R is 4-( CH NC H CO; R is H; Y is CH CH A mixture of 20.3 g. (0.063 mole) of B-[3-(4- aminobenzoy1)-2-methyll -indole]propionic acid, 16.6 g. (0.19 mole) of 34 percent formalin, and 3' g. of percent palladium-on-charcoal in 250 ml. of methanol was shaken with hydrogen in a Parr'shaker under a pressure of about 50 pounds p.s.i. When reduction was complete, the catalyst was removed by filtration, the filtrate was taken to dryness, and the residue recrystallized from ethyl acetate to givel6.5 g. of B-[3-(4- dimethylaminobenzoyl)-2-methyl-1-indole]propionic acid, m.p. l6917l.5C. (uncorr.).

EXAMPLE 41 v a-[3-( 4-Dimethylaminobenzoyl)-2-methyl-1- indole]acetic acid [1: R is H; R5 is CH R is 4(CH NC H CO; R is H; Y-is CH is prepared by reducing with hydrogen over a palladium-on-charcoal catalyst a mixture of a-[3-(4-aminobenzoy1)-2-methyll-indole]acetic acid and formaldehyde and isolation of the product from a neutral medium all according to the procedure described above in Example 40.

EXAMPLE 42 A. 3-( 4-t-Butylbenzoyl)-2-methylindole [11: R is CH R is 4-( CH CC H CO; R is H] is prepared by reaction, in dry ether or tetrahydrofuran, of 4-tbutylbenzoyl chloride with the Grignard reagent prepared from 2-methylindo1e and methyl magnesium bromide using the procedure described above in Example 1A. y B. a-[3-(4-t-Butylbenzoyl)-2-methyl-1-indole1acetic acid [1: R is H; R is CH R is 4(CH CC H CO; R is H; Y is CH is prepared by reaction of ethyl bromoacetate with 3-( 4-t-butyl-benzoy1)- 2-methylindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[ 3-( 4-t-butylbenzoy1)-2-methyl-1-indole]acetate all according to the procedure described above in Example 1B and C.

EXAMPLE 43 B- 3-( 4-t-Butylbenzoyl)-2-methyl-1-indole]propionic acid [I: R, is H; R is CH R is 4(CH CC H CO; R is H; Y is CH CH was prepared by reaction of 9.0 g. 0.099 mole) of ethylB-bromopropionate with 27.5 g. 0.095 mole) of 3 4-t-butylbenzoyl)-2-methylindole in 100 ml. of dry dimethylformamide in the presence of 4. 15 g. (0.10 mole) of a percent suspension of sodium hydride in mineral oil, and saponification of the resulting ethyl B-[ 3-( 4-t-buty1benzoyl)- 2-methyl-l-indolelpropionate all according to the proced ure described above in Example 1B and C. The

crude product was recrystallized twice from benzene to give 16.5 g. of B-[3-( 4-t-butylbenzoy1)- 2-methyl-1-indole]propionic acid, m.p. 165.5168C. uncorr.).

EXAMPLE 44 A. 3-Benzoy1-2,S-dimethylindole [11: R is CH R is C H CO', R is 5CH was prepared by reaction, in dry ether, of 24.4 g. (0.17 mole) of benzoyl chloride with the Grignard reagent prepared from 25 g. (0.17 mole) of 2,5-dimethylindole and a molar equivalent of methyl magnesium bromide using the procedure described above in Example 1A. The crude product was recrystallized from isopropanol to give 24.] g. of 3-benzoyl-2,S-dimethylindole, m.p. 217-2l8C. (uncorr.). I Y

B. a-(3-Benzoyl-2,5-dimethyl-l-indole)acetic acid [1: R, is H; R is CH R is C H CO; R is 5-CH Y is CH is prepared by reaction of ethyl bromoacetate with 3-benzoyl-2,S-dimethylindole in dry dimethylformamidein the presence of sodium hydride and saponification of the resulting ethyl oz-(3-benzoyl-2,5- dimethyl-l-indole)acetate all according to the procedure described above in Example 1B and C.

EXAMPLE 45 B4 3-Benzoyl 2,5-dimethyll -indole )propionic acid [If R1 is R2 iS R is R4 is Y iS I cording to the procedure described above in Example 1B and C. The crude product was recrystallized from acetonitrile to give 175- g. of B-(3-benzoy1-2,5-'

dimethyl-1-indole)-propionic acid, m.p. 2 l2-2l4C. (uncorr.).

EXAMPLE 46 A. 3-(2-Furoyl)-2-rnethy1-6-hydroxyindole [I]: R is CH R is 2C H OCO; R4 is 6-HO] is prepared by reaction, in dry ether or tetrahydrofuran, of 2- furancarbonyl chloride with the Grignard reagent prepared from 2-methyl-6-hydroxyindole and methyl magnesium bromide using the procedure described above in Example 1A. B. y-[ 3-( 2-Furoyl )-2-methyl-6-hydroxyl indole]butyric acid [1: R is H; R is CH5; R 'is 2C H O-CO; R is 6- -HO; Yis (CI-1 h] is prepared by reaction of ethyl y-bromobutyrate with 3-( 2-furoyl)-2 methyl-6-hydroxyindole in drydimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl y-[3-( 2-fur0yl)-2-methyl-6-hydroxyl-indolelbutyrate all according to the procedure described above in Example 1B and C.

EXAMPLE 47 chloride with the Grignard reagent prepared from 2- I with EXAMPLE 48 A. 3-( 3 Pyridinecarbonyl)-2-methyl-6- trifluoromethylindole [I]: R is (CH R is 3C H- N--CO; R is 6-CF is prepared by reaction, in dry ether or tetrahydrofuran, of 3-pyridinecarbonyl chloride with the Grignard reagent prepared from Zmethyl- -trifluorometh'ylindole and methyl magnesium iodide using the procedure described abovejin Example 1A. B. oz-[ 3-] 3-Pyridinecarbonyl )-2-methyl-6- trifluoromethybl-indole]-acetic acid [I: R, is H; R is CH R3 is 3C H.,NCO; R is t5CF Y is CH is prepared by reaction of ethyl bromoacetate with 3-( 3- pyridinecarbonyl)-2-methyl-6-trifluoromethylindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[3-( 3- pyridinecarbonyl )-2-methyl-6-trifluoromethyll indole]acetateall according to the procedure described above in Example 1B and C.

EXAMPLE 49 A. 3-( 4-Pyridinecarbonyl)-2-methyl-5,6- methylenedioxyindole [I]: R is CH; R is 4-C H- N-CO;- R is 5,6-OCH O] is prepared by reaction, indry etheror tetrahydrofuran, of 4-pyridinecarbonyl chloride with the Grignard reagent prepared from 2- methyI- S,6-methylenedioxyindole and methyl magnesium bromide using the procedure described above in Example. lA. I B. a-[3-( 4-Pyridinecarbonyl)e2-methyl-5,6- methylenedioxy-l-indole]-acetic acid [1: R is H; R is CH R is 4-C H NCO; R is 5 ,6-OCH O; Y is CH is prepared by reaction of ethyl bromoacetate with 3- 4-pyridinecarbonyl)f2-methyl-5,6-

methylenedioxyindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[3-(4-pyridinecarbonyl)-2-methyl- 5,6-methylenedioxy-l-indole]acetate all according to the procedure described above in Example 1B and C.

EXAMPLE 50 A. 3-( 4-lsoxazolecarbonyl)-2-methyl-5,6- ethylenedioxyindole [I]: R is CH R is 4-C H- NOCO; R is 5,6OCH CH O] is prepared by reaction, in dry ether or tetrahydrofuran, of 4- isoxazolecarbonyl chloride with the Grignard reagent prepared from Z-methyl-S,6-ethylenedioxyindole and methyl magnesium bromide using the procedure described above in Example 1A. B. a-[ 3-( 4-Isoxazolecarbonyl)-2-methyl-5 ,6- ethylenedioxy-l-indole]-acetic acid [I: R, is H; R is CH R is 4-C H NO-CO; R is 5,6-OCI-] CH O; Y is CH is prepared by reaction of ethyl bromoacetate Y 3-] 4-isoxazolecarbonyl)-2-methyl-5 ,6- ethylenedioxyindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[3-t4-isoxazolecarbonyl)-2-methyl- 5 ,o-ethylenedioxy-l-indole]acetate all according to the procedure described above in Example IB and C.

EXAMPLE 5] A. 3-(4-Thiazolecarbonyl)-2-methylindole [I]: R; is CH R is 4-C H NS-CO; R is H] is prepared by reaction, in dry ether or tetrahydrofuran, of 4- thiazolecarbonyl chloride with the Grignard reagent prepared from Z-methyindole and. methyl magnesium indole]acetic scribed above in Example lB'and C.

EXAMPLE 52 A. 3-1 S-Thiazolecarbonyl)-2-methylindole [11: R is CH R is C H NSCO; R is H] is prepared by reaction, in dry ether or tetrahydrofuran, of 5- thiazolecarbonyl chloride with the Grignard reagent prepared from 2-methylindole and methyl magnesium bromide using the procedure described above in Example 1A. B. a-[3-1 5-Thiazolecarbonyl)-2-methyl-1- indole]acetic acid [1: R, is H; R is CH R is 5-'-C H' NS-CO; R is H; Y is CH is prepared by reactionof ethyl bromoacetate with 3-( 5-thiazolecarbonyl)- 2-methylindole in'dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[ 3-( 5-thiazolecarbonyl)-2-methyl-1- indole]acetate all according to the procedure described above in Example 18 and C.

EXAMPLE 53 A. 3-14 1sothiazolecarbonyl)-2-methylindole [11: R is CH R is 4--C H NSCO; R is H] is prepared by reaction, in dry ether or tetrahydrofuran, of 4- isothiazolecarbonyl chloride with the Grignard reagent prepared from Z-methylindole and methyl magnesium bromide using theprocedure described above in Example 1A. B. a-[ 3-( 4-1sothia zo1ecarbonyl)-2-methyl-1- indole]acetic acid [1: R isH; R is CH R 'is 4--C H EXAMPLE 54 A. 3-( 5-Isothiazolecarbonyl)-2-methylindole [11: R is CH;,; R is 5C H NSCO; R is H] is prepared by reaction, in dry ether or tetrahydrofuran, of 5- isothiazolecarbonyl chloride with the Grignard reagent prepared from 2-methylindole and methyl magnesium bromide using the procedure described above in Example 1A. B. a-[ 3-( 5-1sothiazolecarbonyl )-2-methyll indole]acetic acid [1: R, is H; R is CH R is 5C l-1 NS-CO; R is H; Y is CH isprepared by reaction of ethyl bromoacetate with 3-( 5-isothiazolecarbonyl)- Z-methylindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-l3-(5-isothiazolecarbonyl)-2-methylacid [1: R is H; R is CH R is.

EXAMPLE 55 A. 3- (a-Phenylacetyl)-2-methylindole [11: R is CH R is C H CH CO;R is H] is prepared by reaction. in dry ether or tetrahydrofuran, of phenylacetyl chloride with the Grignard reagent prepared from 2-methylindole and methyl magnesium bromide using the procedure described above in Example 1A.

l-indolelacetate all according to the procedure described above in Example 18 and C..

B. a-[3-( 3-( a-Phenylacetyl)-2-methyll -indole ]acetic acid [1: R is H; R is CH ;-R is C H CH CO; R, is H; Y is CH is prepared by reaction of ethyl bromoacetate with 3-(a-phenylacetyl)-2-methylindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-[3-1 aphenylacetyl)-2-methyl-l-indole]acetate all according to the procedure described above in Example 18 and C.

EXAMPLE 56 A. 2-Methyl-3 phenylindole [11: R is CH R is C H R4 W A mixture of 21.6 g. 0.2 mole) of phenylhydrazine, 26.8 g. (0.2 mole) of phenylacetone, and 50 ml. ofa solution of concentrated aqueous hydrochloric acid in ml.-of absolute ethanol, the whole dissolved in 300 ml. of absolute ethanol, was refluxed on a steam bath for 2 hours, the mixture concentrated to a small volume in vacuo, and the resulting green sludge taken up in water/ether. The organic phase was washed twice with water, and the resulting orange solution was dried and charcoaled. The pale yellow filtrate was taken to dryness in vacuo, and the residual yellow viscous gum distilled in vacuo at 0.5 mm., the product being collected at 143152C. There was thus obtained 34 g. of 2-methyl-3-phenylindole as a yellow viscous oil.

B. Ethyl a-( 2 -rnethyl-3-phenyl-l-indole)acetate [1: R is C H R is CH R is C H R is H; Y is CH ]was prepared by reacting 33.6 g. (0.20 mole) of ethyl bromoacetate with 37 g. (0.18 mole) of 2-methyl-3- phenylindole in the presence of 7.8 g. (0.20 mole) of a'62 percent suspension of sodium hydride in mineral oil in 250 ml. of dimethylformamide using the procedure described above in Example 1B. There was thus obtained 47 g. of ethyl a-1 2-methy1- 3-phenyl-l-indole)acetate as a pale yellow oil.

C. a-( 2-Methyl-3-phenyl-l-indole)acetic acid [1: R is H; R is CH R is C H R is H; Y is CH was prepared by saponifying 47 g. 1 0.l6 mole) of ethyl a-( 2- methyl-3-phenyl-l-indole)-acetate in a solution containing 400 ml. of ethanol and 100 ml. of 35 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized from benzene giving 26 g. of a-( 2- methyl-3-phenyl-1-indole)acetic acid, m. p. l59-167C. (dec.).

In psychomotor activity studies in mice, a-( 2-methyl- 3-phenyl-l-indole)acetic acid was found to depress 74 percent of the motor activity of the test animals at a dose of 300 mg./kg. p.o. Psychomotor depressant activity was determined in standard activity cages using the method of Dews, Brit. J. Pharmacol. 8, 46 1953) in which mice, medicated with the test compound, are

EXAMPLE 57 A. 3-(4-Chlorophenyl)-2-methylindole [[1: R is CH R is 4 ClC H R is H] was prepared by reacting 54 g. 0.5 mole) of phenylhydrazine with 84 g. 0.5 mole) of a-t4-chlorophenyl)-acetone in 750 ml. of absoluteethanol and in the presence of 125 ml. of concentrated hydrochloric acid dissolved in 250 ml. of absolute ethanol using the procedure described above in Example 56A. The crude product was recrystallized from cyclohexane giving 97 g. of 3-(4-chlorophenyl)-2- methylindole, m.p. 1-10-l 115C.

B. Ethyl oz-[ 3-( 4-chlorophenyl)-2-methyll indole]acetate [1: R is C H R is CH R is 4-CIC H R is H; Y is CH was prepared by reacting 25 g. (0.15 mole) of ethyl bromoacetate with 30 g. (0.12 mole) of 3-(4-chlorophenyl)+2-methylindole in the presence of 5.8 g. 0.15 mole) of a 62 percent suspension of sodiumlhydride in mineral oil in 250ml. of dimethylformamide using the procedure described above in Example 1B. There was thus obtained 45 g. of ethyl a- 3-( 4-chlorophenyl)-2 methyl- 1 -indole acetate as a brown oil. I

C. oz-[3-( 4-Chlorophenyl)-2-methyl-1-indole]acetic acid [1: R is H; R is CH R is 4-ClC H R is H; ,Y is CH was prepared by saponification of 46 g. (0.14 mole) of ethyl a-[3-( 4-chlorophenyl)-2-methyl 1- indole]acetate in a solution of 400 ml. of ethanol and 125 ml. of 35 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The

crude product was recrystallized twice from ethanol giving 110 g. of a-[ 3-(4-chlorophenyl)-2-methyl-lindole]acetic acid, m.p. 188202C. (dec.).

EXAMPLE 58 A. Ethyl B4 3-phenyl-2-methyl-l-indole)propionate [1: R1 is C2H5; R2 iS R3 iS CGH5; R4 iS Y lS was prepared by reacting 33 g. (0.20 mole) of ethyl B'bromopropionate with 31.4 g. 0.15 mole) of 3-phenyl-Z-methylindole in the presence of 7.1 g. (0.18 mole) of a 62 percent suspension of sodium hydride in mineral oilin 250 ml. of dimethylformamide usingthe manipulative procedure described above in Example 18. There was thus obtained 46 g. of ethyl B-( 3-phenyl- 2-methyl-1-indole)propionate as a yellow oil. B. B4 3-Phenyl-2-methyl-l-indole)propionic acid [1: R is H; R is CH R is G l-l R is H; Y is CH CH was prepared by saponification of 46 g. 0.27 mole) of ethyl ,B-( 3-phenyl-2-methyl-l-indole)propionate in a solution of 500 ml. of ethanol and 160 ml. of 10 percent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized from ethanol/water giving 21 g. of B-( 3- phenyl-Z-methyll -indole )propionic acid, l35-l37.5C.

B-( 3-Phenyl-2-methyl-l-indole)propionic acid, when tested as a psychomotor depressant as described above in Example 56C, was found to depress percent of the motor activity of the test animals at a dose of 300 mg./kg. (p.o.).

EXAMPLE 59 A. Ethyl B-[-3-( 4-chlorophenyl)-2-methyll indole]propionate '[l: R, is C l-I R is CH R is 4ClC H R is H; Y is CH CH was prepared by reacting 20 g. (0.083 mole) of 3-(4-chlorophenyl)- Zmethylindole with 16.5 g. (0.091 mole) of ethyl B-bromopropionate in ml. of dry dimethylformamide in the presence of 3.62 g. (0.092 mole) of a 61 percent suspension of sodium hydride in mineral oil using the procedure described above in Example 18. There was thus obtained ethyl B-['3-(4-chlorophenyl)- 2-methyl-1-indole]propionate.

B. B-[3-(4-Chloro phenyl)-2-methyl-lindole]propionic acid [I: R is H; R is CH R is 4ClC H R is H; Y is CH CH was prepared by saponification of the ethyl B-[3-(4-chlorophenyU-2- methyl-l-indole]propionate obtained above in Example 59A in a solution containing 30 g. of potassium hydroxide dissolved in 200 ml. of methanol using the procedure described above in Example 1C. The crude product was recrystallized from benzene giving 8.4 g. of B-[3-( 4-chlorophenyl)-2-methyl-1-indole]propionic acid, m.p. 143.5-l45.5C.

EXAMPLE 60 A. 3-( 4-Hydroxybenzyl)-2-methylindole [[1: R is CH R is 4HOC H CH R is H] is prepared by reacting 2-( 4-hydroxyphenyl)-ethyl methyl ketone with phenylhydrazine in ethanol in the presence of hydrochloric acid using the procedure described above in Example 56A. The product is reacted with acetic anhydride in the presence of pyridine to give 3-( 4-acetoxybenzyl)-2- methylindole [llz R is CH R is 4-CH- B. a-[3-(4-Hydroxybenzyl)-2-methyl1-indole]acetic acid [I: R and R are H; R is CH R is 4-- HOC H CH Y is CH is prepared by reacting ethyl bromoacetate I with 3-( 4-hydroxybenzyl)-2- methylindole in dry dimethylformamide in the presence of sodium hydride, and sapoinification of the resulting ethyl a-[3-( 4-hydroxybenzyl)- 2-methyl-l-indole]acetate all according to the procedure described above in Example 13 and C.

Similarly reaction of ethyl bromoacetate with 3-( 4- acetoxybenzyl)-2-methylindole in dry dimethylformamide in the presence of sodium hydride affords ethyl a-[3-( 4-acetoxybenzyl)-2-methyll -indole lacetate [l. R1 iS C2H5; R2 is R3 iS R4 is H; Y is CH EXAMPLE 61 A. 3-Benzyl-2-methylindole [11: R is CH R is C H CH R is H] is prepared by reacting 2- phenylethyl methyl ketone with phenylhydrazine in ethanol in the presence of hydrochloric acid using the procedure described'above in Example 56A.

B. oz-( 3-Benzyl-2-methyl-l-indole)acetic acid [1: R is H; R is CH R is C H CH R is H; Y is CH is prepared by reacting ethyl bromoacetate with 3-benzyl-2- methylindole in dry dimethylformamide in the presence of sodium hydride, and saponification of the resulting ethyl a-( 3-benzyl-2-methyl-l-indole)acetate all according to the procedure described above in Example 1B and C.

EXAMPLE 62 A. 3'-(4-Chlorobenzyl)-2-methylindo1e [11: R is CH In two separate runs, 25 g. (0.093 mole) and 40 g.

(0.15 mole) of 3-(4-chlorobenzoyl)-2-methylindole,

dissolved in 250 ml. and 350 ml. portions, respectively, of 'tetrahydrofuran was added in each case to a solution containing 0.25 mole of diborane in 250ml.of tetrahydrofuran. The reaction mixtures wererefluxed in each EXAMPLE 65 y-( 3-Benzoyl-2-methyl-1, indole)butyric acid [laz R is H; R is CH R is C H CO; Y is (CH was prepared case for 1% hours, cooled to room temperature, and

the excess diborane destroyed by the addition of a small 'arnountv of water. The two solutions where then combined, taken to dryness in vacuo, the residual material taken up in about 1.5 liters of ethylacetate, the organic solution washed with water, then with brine, dried, and taken to dryness giving 64 g. of 3-( 4- chlorobenzyl)-2-methylindole.

B. Ethyl a-[ 3-( 4-chlorobenzyl)-2-methyl-1- indole]acetate [1: R is (C 11 R is CH R is 4--ClC H CH R is H; Y is CH was prepared by reaction of ethyl bromoacetate with 18.4 g. 0.11 mole) of 3-(4-chlorobenzyl)-2-methy1indo1e in the presence of 5.1 g. (0.11 mole) of a 52 percent suspension of sodium hydride in mineral oil in 250 ml. of dry dimethylformamide using theprocedure described above in Example 13. There was thus obtained 30 g. of ethyl a-[3- 4-chlorobenzyl)-2 methyl-l -indole]acetic acid as a red-brown oil. C. a-[ 3-( 4-Chlorobenzyl) -2-methy1- 1 -indole acetic acid [1: R is H; R is CH R is 4ClC H CH- R is H; Y is CH was prepared by saponification of '30 g. (0.088 mole) of ethyl a-[3-( 4-chlorobenzyl)-2 methyll-indole]acetate in a solutionof 800 ml. of ethanol and 200 ml. of IOpercent aqueous sodium hydroxide using the procedure described above in Example 1C. The crude productwas recrystallized from benzene giving 7.3 g. of a-[3-(4-chlorobenzyl)-2-methy1-1- indolelacetic acid, m.p. 202-205C.

EXAMPLE 63 EXAMPLE 64 ,3.- 3-( 4-Acetylaminobenzoyl)-2-methyl-1- indole]propionic acid [1: R is H; R is CH R is A mixture of 6.3 g. (0.018 mole) of ethyl B-[3-(4- aminobenzoyl)-2-methyl-1-indole]propionate and 25 ml. of acetic anhydride was warmed to 60C. on a steam bath. The mixture, which deposited a copious precipitate, was treated with water, heated-to reflux, cooled, and the solid which separated was collected and washed with water to give 1 1 g. of a cream colored by reaction of 9.6 g. 0.05 mole) of ethyl y-bromobutyrate with 11 g. 0.05 mole) of 3-benzoyl-2- methylindole in 80 ml. of dimethyl'formamide in the presence of 2.06 g. (0.05 mole) of a 60 percent suspension of sodium hydride using the procedure described above in Example 13, and saponification of the resulting ethyl 7-( 3-benzoyl-2-methyl-1-indole)butyrate, obtained as a brown gum, in ml. ofmethanol containing 15 g. of potassium hydroxide using the procedure described above in Example 1C. The crude product was recrystallized two times from ethyl acetate to give 6.1 g. of y-( 3-benzoyl-2-methyl-1-indole)butyric acid, melts partly at 132135C., melts completely at 151-153 C.

EXAMPLE 66 'y-[ 3-( 2-Furoyl)-2-methyl-6-acetoxy-1-indole]butyric acid [1: R is H; R is CH;,; R is 2C H O--CO; R is 6-CH COO; Y is (CH is prepared by reaction of y-[ 3-( 2-furoyl)-2-methyl-6-hydroxy-1-indole]butyric acid with acetic anhydride in the presence of pyridine.

EXAMPLE 67 a-.[3-( 2-Thenoyl)-2 ,-methyl-1-indo1e]propionic acid [1: R is H; R is CH R is 2C H SCO; R is H; Y is CH CH] was prepared by reaction of 10 g. (0.042 mole) of 3-( 2-thenoyl)-2-methylir1dole with 7.5 g. (0.042 mole) of ethyl a-bromopropionate in 100 ml. of dry dimethylformamide in the presence of 1.65 g. of a 60 percent suspension of sodium hydride in mineral oil and saponification of the crude product, ethyl a-[3-( 2- thenoyl)-2-methyll -indole]propionate, with methanolic alkali using the procedure described above in Example 1B and 1C. The product thus obtained was recrystallized from an ethyl acetate/benzene mixture giving 48 g. of a-[3-(2-thenoyl)-2-methyl-1-indole]propionic acid, mp. 185-189C.

EXAMPLE 68 A. 3-Benzoyl-2,4-dimethylindole [11: R is CH R is C H CO; R is 4CH was prepared by reaction of 14.0 g. 0.1 mole) of benzoyl chloride in 50 ml. of ether with the Grignard reagent prepared from 14.52 g. (0.1 mole) of 2,4-dimethylindole and 33ml. (0.099 mole) of a 3M ether solution of ethyl magnesium bromide in a total volume of about ml. of absolute ether using the procedure described above in Example 1A. There was thus obtained 14.2 g. of 3-benzoyl-2,4- dimethylindole, m.p. 174-175C. uncorr.).

B. /3-( 3-Benzoyl-2,4-dimethyl-1-indole)propionic acid [1: R is H; R is CH R is C H CO; R is 4CH Y is CH CH was prepared by reacting 9 g. (0.036 mole) of 3-benzoyl-2,4-dimethylindole with 6.5 g. 0.06 mole) of ethyl B-bromopropionate in 100 ml. of dry dimethylformamide in the presence of 1.6 g. (0.04 mole) of a 60 percent suspension of sodium hydride in mineral oil and saponification of the resulting crude product, ethyl B4 3-benzoyl-2,4-dimethy1-1- indole)propionate, with methanolic alkali using the procedure described above in Example 13 and 1C. The product thus obtained was recrystallized twice from acetonitrile giving 6.64 g. of B-( 3-benzoyl-2,4-dimethyl- 1-indole)propionic acid, m.p. 187-l88C. (uncorr.).

' EXAMPLE 69 A. 3-'(3,4-Dimethylbenzoyl)-2 methylindole [11: R is CH R is 3,4-( CH C H CO; R is H] was prepared by reaction of 25.2 g. (0.15 mole) of 3,4- dimethylbenzoyl chloride in 50 ml. of ethyl ether with the Grignard reagent prepared from 19.6 g. (0.15

mole) of 2-methylindole and 52.5 ml. (0.16 mole) of a 34 dimethylbenzoyl)-2-rnethyl-1-indole]propionic m.p. 1'52 154C. (uncorr.).

EXAMPLE 71 A. 3-(4-Methyl-3-fluorobenzoyl)-2-methy1indo1e [11: R is CH R is 4CH --3--FC H CO; R is H] was prepared by reaction of 27.2 g. (0.16 mole) of 4-methyl-3-fluorobenzoyl chloride in 100 ml. of ether with the Grignard reagent prepared from 20.7 g. (0.16 mole) of 2-methylindole and 55 ml. (0.17 mole) of a 3M solution of ethyl magnesium bromide in absolute ether using the procedure described above in Example 1A. The crude product thus obtained was recrystallized from ethyl acetate giving 15.7 g. of 3-(4-methyl-3- fluorobenzoyl)-2-methy1indo1e, m.p. 209210.5C. (uncorr.).

B. /3-[3 4-Methyl-3-fluorobenzoyl )-2-methyll indole]propionic acid [1: R, and R are H; R is CH R acid,

1 is 4-CH 3-FC H CO; Y is CH CH was prepared by reaction of 19.55 g. 0.073 mole) of 3-(4-methyl-3- fluorobenzoyl)-2-methylindole with 13.9 g. 0.077 mole) of. ethyl B-bromopropionate in 100 m1. of dry dimethylformamide in the presence of 3.2 g. (0.08 mole) of a 60 percent suspension of sodium hydride in rnin-' eraloil and saponification of the crude product, ethyl B- 3-( 4-methyl-3-tluorobenzoyl)-2-methyl-1 indole]propionate, with methanolic alkali using the procedure described above in Example 1B and 1C. The

mole) of a 61 percent suspension of sodium hydride in mineraloil and saponification of the product, ethyl B-[- 3-( 3 ,4-dimethylbenzoyl )-2-methyl- 1 indole]propionate, with methanolic sodium hydroxide using the procedure described above in Example 1B and 1C. The material thus obtained was recrystallized from acetonitrile giving 10.5 g. of B-[3-(3,4- dimethylbenzoyl)-2 methyl- 1 -indole ]propionic acid, m.p. 182-185C. (uncorr.).

EXAMPLE 70 A. 3-( 3,5:Dimethylbenzoyl)-2-rnethylindole[11: R5 is CH R is 3,5(.CH C H C 0; R is H] was prepared by reaction of 37.6 g. (0.2 mole) of 3,5- dimethylbenzoyl chloride in 100 ml. of ether with the Grignard reagent prepared from 26.2 g. 0.2 mole) of Y pared by reaction of 26 g. (0.1 mole) of 3-(3,5-

dimethylbenzoyl)-2-rnethylindole with 19 g; (0.11 mole) of ethyl B-bromopropionate in 150 ml. of dimethylformamide in the presence of 4.35 g. 0.11 mole) of a 61 percent suspension of sodium hydride in mineral oil and saponitication of the crudeproduct, ethyl B-[3-( 3 ,S-dirnethylbenzoyl)-2-methyl- 1 indole]propionate, with methanolic sodium hydroxide using the procedure described above in Example 1B and 1C. The material thus obtained was recrystallized from acetonitrile giving 14 g. of B-[3-(3,5-

crude product was isolated from an acidic medium and recrystallized from acetonitrile giving,l7.3 g. of B-[3- 4-methyl-3 fluorobenzoyl)-2-methyl 1-indole] propionic acid, m.p. 193-196C. (uncorr.).

EXAMPLE 72 A. 3-(4-fluorobenzoy1)-2methylindole [11: R is CH R is 4FC H CO; R is H] was prepared by reaction of 25g. (0.16 mole) of 4-fluorobenzoyl chloride in 150 ml. of absolute etherwith the Grignard reagent prepared from 20.7 g. 0.16 mole) of 2-methylindole and 55 ml. (0.17 mole) of a 3Mether solution of ethyl magnesium bromide in a total of about 250 ml. of ether. The crude product was recrystallized from ethyl acetate to give 17 g. of 3-( 4fluorobenzoyl)-2-methylindole as pink crystals.

B. B-[ 3-( 4-Fluorobenzoyl )-2-methyll indole]propionic acid [la: R is H; R is CH R is 4-FC H CO; Y is CH CHflwas prepared by reacting 16.5 g. 0.065 mole) of 3-( 4-fluorobenzoy1)-2- methylindole with 12.4 g. (0.068 mole) of ethyl B-bromopropionate in 75 ml. of dry dimethylformamide in the presence of 2.84 g. (0.072 mole) of a 61 percent suspension of sodium hydride in mineral oil and saponification of the crude product, ethyl [3-[3-( 4- fltroroben'zoyU-Z-methyl-l-indole]propionate, with methanolic alkali using the procedure described above in Example 113 and 1C. The product was isolated from an acidic medium and recrystallized from acetonitrile giving 14.5 g. of B-[3-(4-fluorobenzoyl)-2-methyl-1- indolelpropionic acid, m.p. 215219C. (uncorr.).

EXAMPLE 73 A. 3- 3-Fluorobenzoyl)-2-methylindole [11: R is CH R is'3-FC H CO; R is H] was prepared by reaction of 31.6 g. 0.20 mole) of 3-fluorobenzoy1 chloride in ml. of absolute ether with the Grignard reagent.

prepared from 26.2 g. (0.20 mole) of 2-methy1indole and 70 ml. 0.21 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 270 m1. of absolute ether using the procedure described in Example 1A. The crude product was recrystallized from ethyl acetate giving 23 g. of 3-( 3-fluorobenzoyl)-2- methylindole as cream colored crystals.

B. B-[ 3-( 3-Fl uorobenzoyl)-2-methyl-1- indole]propionic acid [lar R is H; R is CH R is 3FC H CO; Y is CH CH was prepared by reacting methanolic alkali using the procedure described above in Example 18 and 1C. The product was isolated from an acidic medium and recrystallized from acetonitrile giving 15.7 of B-[3-(3-fluorobenzoyl)-2-methyl-1- indole]propionic' acid, m.p. 179-181'.5C. (uncorr.).

. EXAMPLE 74 A. 3-(2,4,6 Trimethylbenzoyl)-2-methylindole 11; R is CH3; R3 is 2,4,6(CH3)3C6H2CO; R4 is H] was pre pared by reaction of 40 g. (0.22 mole) of 2,4,6- trimethylbenzoyl chloride in .50 m1. of ethyl ether with the Grignardreagent prepared from 28.8 g. (0.22 mole) of Z-methylindole and 77.5 ml. (0.23 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 275 ml. ofabsolute ether using the procedure described above in Example 1A; There was thus obtained 54 g. of 3-( 2,4,6-trimethylbenzoyl)-2- methylindole, a small sample of which was recrystallized from ethyl acetate to .give material. of m.p. 26 1268 C. uncorr.).

B. /3-[ 3,-( 2 ,4,6-Trimethylbenzoyl)-2-methyl-1- indole]propionic acid [1: R and R are H; R is CH R is 2,4,6(-CH C H CQ; Y is CH CH was prepared by reacting 20 g. (0.073 mole) of 3-(2,4,6- trimethylbenzoyl)-2-methylindole with 13.8 g. (0.76 mole) of ethyl B-bromopropionate in 200 ml. of dry dirnethylformamide in the presence of 3.16 g. (0.079 mole) of a 61 percent suspension of sodium hydride in mineral oil and saponification of the product, ethylB-[- 3-( 2,4,6-trimethylbenzoyl)-2-methyl-1- indole]propionic acid, with methanolic alkali. The crudeproduct was isolated from an acidic medium and recrystallizedfrom acetonitrile giving 14.8 g. of [3-[3- 2,4,6-trimethylbenzoyl)-2-methyl-1-indole]propionic acid, m.p. l50-152.5C. (uncorr.).

EXAMPLE 75 A. 3-( 4-Ethylbenzoyl)-2-methylindole [11: R is CH R is 4--C H C H CO; R is H] was prepared by reaction of 29.7 g. (0.18 mole) of 4-ethylbenzoyl chloride in 150 ml. of absolute ether with the Grignard reagent prepared from 27.8 g. 0.211 mole)-of 2-methylindole and 71 ml. 0.21 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 27 0 ml. of absolute ether using the procedure'described above in Example 1A. The crude product was recrystallized from ethyl acetate giving 24 g. of 3-(4-ethylbenzoyl)-2-.

methylindole- B. [H 3-( 4-Ethylbenzoyl )-2-methyl- 1 -indole]propionic acid [I: R, and R are H; R is CH R is 4--C l-1,,C H-

- C0; Y is CH CH was prepared by reaction of 23 g.

(0.088 mole) of 3-( 4-ethylbenzoyl)-2-methylindole with 16.6 g. (0.092 mole) of ethyl B-bromopropionate EXAMPLE 76 A.3 Cyclohexylcarbonyl-2-methylindole [II: R is CH R is C H CO; R is H] was prepared by reaction of 29.2 g. (0.2 mole) of cyclohexane carbonyl chloride with the Grignard reagent prepared from 26.2 g. 0.2 mole) of 2-methylindole and 73.5 ml. 0.22 mole) of a 3M ether solution of ethyl magnesium bromide in a totalvolume of about 275 ml. of absolute ether. The crude product was recrystallized from benzene giving 20.5 g. of '3 cyclohexylcarbonyl-Z-methylindole asa cream colored solid.

B. ,8-[ 3-Cyclohexylcarbonyl-2-methyll indole]propionic acid [1: R and R are H; R is CH R is C H CO;'Y is CH CH was prepared by reaction of 20.5 g. (0.085 mole) of 3-cyclohexylcarbonyl-2- methylindole with 16.2- g. (0.089 mole) of ethyl B-bromopropionate in ml. of dimethylformamide in the presence of 3.73 g. 0.094 mole) of a 60 percent suspension ofsodium hydride in mineral oil and saponi- EXAMPLE 77 A. 3-( 3-Methylbenzoyl)-2-methylindole [11: R is CH R is 313 CH C H CO; R is H] was prepared by reaction of 38.6 g. (0.25 mole) of 3-methylbenzoyl chloride in 100 ml. of diethyl ether with the Grignard reagent prepared from 32.9 g. (0.25 mole) of Z-methylindole and 92 ml. 0.28 mole) of a 3M ether solution of ethyl magnesium bromide in a total volume of about 300 ml. of diethyl ether. The crude product was recrystallized from acetonitrile giving 39 g. of 3-( 3-methylbenzoyl)- 2-methylindole.

B. B-[3-( 3-Methylbenzoyl)-2-methyl-1- indole]propionic acid [I: R and R are H; R is CH R is 3CH C H.,CO; Y is CH CH was prepared by reacting 38 g. 0.15 mole) of 3-( 3-methylbenzoyl)-2- methylindole with 29 g. 0.16 mole) of ethyl B-bromopropionate in 200 m1. of dimethylformamide in the presence of 6.7 g. 0.17 mole) of a 60 percent suspension of sodium hydride in mineral oil and saponification of the resulting ester, ethyl B-[3-( 3-methylbenzoyl)-2- methyl-l-indolelpropionate, with methanolic alkali using the procedure described above in Example 18 and 1C. Recrystallization of the crude product thus obtained from acetonitrile gave 24.6 g. of B-[3-( 3- methylbenzoyl )-2-methyll -'indole ]propionic acid, m.p. -173C. (uncorr.).

EXAMPLE 78 A. 3-( 3,4-Dimethoxybenzoyl)-2-methylindole [11: R is CH R is 3,4(CH O) C H CO; R is H] was prepared by reaction of 90 g. v 0.45 mole) of 3,4- dimethoxybenzoyl chloride in 150 ml. of tetrahydrofuran with the Grignard reagent prepared from 59 g. 0.45 mole) of 2-methylindole and 165 ml. (0.50 mole) of a 3M ether solutionof ethyl magnesium bromide in a total of 565 ml. of absolute ether. The crude product was recrystallized oncefrom ether and once from benzene giving 47 g. of 3-( 3,4-dimethoxybenzoyl)-2- methylindole. I B. B-[3-( 3,4-Dimethoxybenzoyl)-2-methyll indole]propionic acid [lap R is H; R is CH R is 3,4--( CH O) C H CO; Y, is CH Cl-l was prepared by reaction of 47 g. 0.16 mole) of 3-( 3,4-dimethoxybenzoyl)-2-methylindole with 30.8 g. (0.l7 mole) of ethyl ,B-bromopropionatein 150 ml. of dry dimethylformamide in the presence of 7 g. (0.18 mole) of a 60 percent suspension of sodium hydride in mineral oil and saponification of the resulting ester, ethyl B.-[3-(3,4-

'dimethoxybenzoyl )-2-methyl- 1 -indole propionate,

with methanolicalkali using the procedure described above in Example 113 and 1C. The crude product thus obtained was recrystallized from benzene giving 1 1.3 g. of /3-[ 3-( 3 ,4-dimethoxybenzoyl)-2-methyl-1-indole]- propionic acid, m.p. 143 l45.5C. uncorr.).

EXAMPLE 79 A. 3-(l-Adamantanecarbonyl)-2-methylindo1e [11: R is CH R is l-adam'antane-CO; R is H] was prepared by reaction of 25 g. (0.13 mole) of ladamantanecarboxylic acid chloride in 150 ml. of ether with the Grignard reagent prepared from 20.7 g. 0.16 mole) of Z-methylindole and 55 ml. 0.17 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 300 ml. of absolute ether using the procedure described above in Example 1A. The crude product was recrystallized once from an ether/hexane mixture and once from benzene giving 6.9 g'. of 3-(1 adamantanecarbonyl)-2-methylindole, m.p. 155-158C. (uncorr.).

B. B- 3-( l-Adamantanecarbonyl)-2-methyl-1- indole]propionic acid [1: R, and R are H; R is CH R is l-adamantane-CO; Yis CH CH was prepared by reaction of 11.5 g. (0.039 mole) of 3-H- adamantanecarbonyl)'2-methylindole with 7.45. g. 0.041 mole) of ethyl ,B-bromopropionate in 100 ml. of dry dimethylformamide in the presence of 1.72 g. (0.43 mole) of a 60 percent suspension of sodium hydride in V mineral oil and saponification of the resulting ester,

ethyl B-[ 3-( l-adamantanecarbonyl)-2-methyl-1- indole]propionate, with methanolic alkali using the procedure described above in Example lBand 1C. The crude product was recrystallized from benzene giving 4.6 g. of B-[3-( 1-adamantanecarbonyl)-2-methyl-1- indole]propionic acid, m.p. 169" 171C. uncorr.

EXAMPLE so A. 3-(4-Biphenylcarbonyl)-2-methylindole [lI: R is CH;,; R is 4-C H -'-C H C0; R is H] was prepared by reaction of 43.2 g. (0.20 mole) of 4- biphenylcarbonyl chloride in 200 ml. of tetrahydrofuran with theGrignard reagent prepared from 26.2 g. (0.2 mole) of 2-methylindole and 73.5 ml. (0.22 mole) of a 3M solution of ethyl magnesium bromide in a total of about 275 ml. of dry ether. The crude product was recrystallized from acetonitrile giving 22 g. of 3(4- 38 biphenylcarbonyl)-2-methylindole, mp. 222224C. uncorr. I B B-[ 3-( 4-Biphenylcarbonyl )-2-methyll biphenylcarbonyl)-2-methyl-l-indole1propionate, with methanolic alkali using the procedure described above in Example 1B and 1C. The crude product thus obtained was recrystallized twice from acetonitrile giving 16.5 g. of B-[3-( 4-biphenylcarbonyl)-2-methyl-1- indole]propionic acid, m.p. l7l.5174C. uncorr.).

. EXAMPLE 81.

A. 3-Cyclopentylcarbonyl-Z-methylindole [11: R is CH R is C H CO; R is H] was prepared by reaction of 34 g. (0.26 mole) of cyclopentane carboxylic acid chloride'with the Grignard reagent prepared from 40 g. 0.31 mole) of Z-rnethylindole and 107 ml. 0.32 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 300 ml. of absolute ether using the procedure described above in Example 1A. The crude product was recrystallized from benzene giving 15 g. of 3-cyclopentylcarbonyl-2-methylindole as an off-white solid.

B. B-[ 3-Cyclopentylcarbonyl-2-methyll indole]propionic acid [1; R and R are H; R is CH R is C H CO; Y is CH CH was prepared by reaction of 22.1 g. 0.097 mole) of 3-cyclopentylcarbonyl-2- methylindole with 18.5 g. (0.102 mole) of ethyl B-bromopropionate in 150 ml. of dimethylformamide v in the presence of 4.27 g. (0.107 mole) of a 60 percent suspension of sodium hydride in mineral oil and saponification of the resulting ester, ethyl B-[3- cyclopentylcarbonyl-2-methyl-1-ir1dole]propionate, with methanolic alkali using the procedure described above inExample 1B and 1C. The crude product thus obtained was recrystallized from a benzene/hexane mixturegiving 8.5 g. of B-[3-cyclopentylcarbonyl-2- methyl-l.-indole]propionic acid, 'm.p. l38-l40.5C. (uncorr.).

EXAMPLE 82 A. 3-( 2,4-Dimethoxybenzoyl)-2-methylindole [11: R is CH3; R3 is R4 iS was prepared by reaction of 83 g. (0.42 mole) of 2,4- dimethoxybenzoyl chloride with the Grignard reagent prepared from 54.5 g. (0.42 mole) of 2-methylindole and 152 ml. 0.46 mole) of a 3M ether solution of ethyl magnesium bromide in a total of about 550 ml. of abso- 

1. A-(3-(4-CHLOROBENZOYL)-2-METHYL-6-METHOXY-1-INDOLE)ACETIC ACID. 